EP0573562B1 - Dihydroquinoline NMDA antagonists - Google Patents
Dihydroquinoline NMDA antagonists Download PDFInfo
- Publication number
- EP0573562B1 EP0573562B1 EP92907466A EP92907466A EP0573562B1 EP 0573562 B1 EP0573562 B1 EP 0573562B1 EP 92907466 A EP92907466 A EP 92907466A EP 92907466 A EP92907466 A EP 92907466A EP 0573562 B1 EP0573562 B1 EP 0573562B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- represented
- hydrogen
- alkyl
- dihydroquinoline
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000005557 antagonist Substances 0.000 title abstract description 5
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 title abstract description 4
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 167
- 239000001257 hydrogen Substances 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 56
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 51
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 30
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 28
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 28
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 claims description 22
- 229960003081 probenecid Drugs 0.000 claims description 21
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 230000004770 neurodegeneration Effects 0.000 claims description 10
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 9
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 9
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 230000006378 damage Effects 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 208000019695 Migraine disease Diseases 0.000 claims description 5
- 230000003042 antagnostic effect Effects 0.000 claims description 5
- 206010027599 migraine Diseases 0.000 claims description 5
- 206010021143 Hypoxia Diseases 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 230000002461 excitatory amino acid Effects 0.000 claims description 4
- 239000003257 excitatory amino acid Substances 0.000 claims description 4
- 230000001146 hypoxic effect Effects 0.000 claims description 4
- 230000000302 ischemic effect Effects 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 19
- 230000002490 cerebral effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- 150000004702 methyl esters Chemical class 0.000 description 103
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- 238000010992 reflux Methods 0.000 description 60
- 238000003756 stirring Methods 0.000 description 45
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 32
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 27
- 239000000376 reactant Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- BGKFPRIGXAVYNX-UHFFFAOYSA-N 5,7-dichloro-4-oxo-1H-quinoline-2-carboxylic acid Chemical compound ClC1=CC(Cl)=CC2=NC(C(=O)O)=CC(O)=C21 BGKFPRIGXAVYNX-UHFFFAOYSA-N 0.000 description 15
- 229940124530 sulfonamide Drugs 0.000 description 15
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- -1 C(O)NR1R2 Chemical compound 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 150000003456 sulfonamides Chemical class 0.000 description 11
- 0 *C(Nc1c2c(Cl)cc(Cl)c1)=CC2=N* Chemical compound *C(Nc1c2c(Cl)cc(Cl)c1)=CC2=N* 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical class C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 206010010904 Convulsion Diseases 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- JHRWWRDRBPCWTF-OLQVQODUSA-N captafol Chemical compound C1C=CC[C@H]2C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)[C@H]21 JHRWWRDRBPCWTF-OLQVQODUSA-N 0.000 description 7
- CEZWFBJCEWZGHX-UHFFFAOYSA-N 4-isocyanato-n-(oxomethylidene)benzenesulfonamide Chemical compound O=C=NC1=CC=C(S(=O)(=O)N=C=O)C=C1 CEZWFBJCEWZGHX-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 125000004663 dialkyl amino group Chemical group 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000003368 amide group Chemical group 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- BUXTXUBQAKIQKS-UHFFFAOYSA-N sulfuryl diisocyanate Chemical compound O=C=NS(=O)(=O)N=C=O BUXTXUBQAKIQKS-UHFFFAOYSA-N 0.000 description 5
- YAZSBRQTAHVVGE-UHFFFAOYSA-N 2-aminobenzenesulfonamide Chemical compound NC1=CC=CC=C1S(N)(=O)=O YAZSBRQTAHVVGE-UHFFFAOYSA-N 0.000 description 4
- FJESHSZKRZNZRO-UHFFFAOYSA-N 2-isocyanato-n-(oxomethylidene)benzenesulfonamide Chemical compound O=C=NC1=CC=CC=C1S(=O)(=O)N=C=O FJESHSZKRZNZRO-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 150000003248 quinolines Chemical class 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- LQNMRWXRGXHRPP-UHFFFAOYSA-N 5-bromo-7-fluoro-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound BrC1=CC(F)=CC2=NC(C(=O)O)=CC(O)=C21 LQNMRWXRGXHRPP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 150000001408 amides Chemical group 0.000 description 3
- 230000000949 anxiolytic effect Effects 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000004508 fractional distillation Methods 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- UJYAZVSPFMJCLW-UHFFFAOYSA-N n-(oxomethylidene)benzenesulfonamide Chemical compound O=C=NS(=O)(=O)C1=CC=CC=C1 UJYAZVSPFMJCLW-UHFFFAOYSA-N 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- KDAMMLMNJOOSEG-UHFFFAOYSA-N 1,1,1-trifluoro-n-(oxomethylidene)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N=C=O KDAMMLMNJOOSEG-UHFFFAOYSA-N 0.000 description 2
- LIVDQXZAOVGGGQ-UHFFFAOYSA-N 1-bromo-3-ethyl-5-nitrobenzene Chemical compound CCC1=CC(Br)=CC([N+]([O-])=O)=C1 LIVDQXZAOVGGGQ-UHFFFAOYSA-N 0.000 description 2
- DWJZKFOPEMAJMS-UHFFFAOYSA-N 2-bromo-4-ethyl-6-nitroaniline Chemical compound CCC1=CC(Br)=C(N)C([N+]([O-])=O)=C1 DWJZKFOPEMAJMS-UHFFFAOYSA-N 0.000 description 2
- HCYDUPDSEDHSQB-UHFFFAOYSA-N 2-bromo-4-fluoro-6-nitroaniline Chemical compound NC1=C(Br)C=C(F)C=C1[N+]([O-])=O HCYDUPDSEDHSQB-UHFFFAOYSA-N 0.000 description 2
- JLVFFMBMJKDTFD-UHFFFAOYSA-N 2-chloro-4-isocyanato-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC(N=C=O)=CC=C1S(=O)(=O)N=C=O JLVFFMBMJKDTFD-UHFFFAOYSA-N 0.000 description 2
- YPAQYCIEIXDIQG-UHFFFAOYSA-N 3-bromo-5-ethylaniline Chemical compound CCC1=CC(N)=CC(Br)=C1 YPAQYCIEIXDIQG-UHFFFAOYSA-N 0.000 description 2
- NGZAVSDIXFIWHJ-UHFFFAOYSA-N 3-bromo-5-fluoroaniline Chemical compound NC1=CC(F)=CC(Br)=C1 NGZAVSDIXFIWHJ-UHFFFAOYSA-N 0.000 description 2
- HSQJQLSCIQNBSX-UHFFFAOYSA-N 3-chloro-4-isocyanato-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC(S(=O)(=O)N=C=O)=CC=C1N=C=O HSQJQLSCIQNBSX-UHFFFAOYSA-N 0.000 description 2
- BUFPYFZTTSMGCN-UHFFFAOYSA-N 3-chloro-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)N=C=O)=C1 BUFPYFZTTSMGCN-UHFFFAOYSA-N 0.000 description 2
- TVHXQQJDMHKGGK-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 TVHXQQJDMHKGGK-UHFFFAOYSA-N 0.000 description 2
- LFLSATHZMYYIAQ-UHFFFAOYSA-N 4-flourobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(F)C=C1 LFLSATHZMYYIAQ-UHFFFAOYSA-N 0.000 description 2
- FHMRJRSOWRCSKA-UHFFFAOYSA-N 4-fluoro-n-(oxomethylidene)benzenesulfonamide Chemical compound FC1=CC=C(S(=O)(=O)N=C=O)C=C1 FHMRJRSOWRCSKA-UHFFFAOYSA-N 0.000 description 2
- RGVBEISMHCYSNF-UHFFFAOYSA-N 4-methoxy-n-(oxomethylidene)benzenesulfonamide Chemical compound COC1=CC=C(S(=O)(=O)N=C=O)C=C1 RGVBEISMHCYSNF-UHFFFAOYSA-N 0.000 description 2
- MSFQEZBRFPAFEX-UHFFFAOYSA-N 4-methoxybenzenesulfonamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1 MSFQEZBRFPAFEX-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 206010043994 Tonic convulsion Diseases 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- KIGVMGGSKQAQDF-UHFFFAOYSA-N ethyl 7-bromo-5-ethyl-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(Br)C=C2NC(C(=O)OCC)=CC(=O)C2=C1CC KIGVMGGSKQAQDF-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- UBDGBFBBHDYKSS-UHFFFAOYSA-N n-(oxomethylidene)-4-(trifluoromethyl)benzenesulfonamide Chemical compound FC(F)(F)C1=CC=C(S(=O)(=O)N=C=O)C=C1 UBDGBFBBHDYKSS-UHFFFAOYSA-N 0.000 description 2
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical class C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SWXVEPMSQBEVRH-UHFFFAOYSA-N 1-bromo-3-fluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=CC(Br)=C1 SWXVEPMSQBEVRH-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- HCMQCNNTMBBVLX-UHFFFAOYSA-N 2-aminobenzenesulfonyl chloride Chemical compound NC1=CC=CC=C1S(Cl)(=O)=O HCMQCNNTMBBVLX-UHFFFAOYSA-N 0.000 description 1
- LALCDSDHLXWTTL-UHFFFAOYSA-N 2-chloro-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC=CC=C1S(=O)(=O)N=C=O LALCDSDHLXWTTL-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- WSYQJNPRQUFCGL-UHFFFAOYSA-N 3-chlorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(Cl)=C1 WSYQJNPRQUFCGL-UHFFFAOYSA-N 0.000 description 1
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 1
- NIDOTDANGJJHPU-UHFFFAOYSA-N 4-amino-2-chlorobenzenesulfonamide Chemical compound NC1=CC=C(S(N)(=O)=O)C(Cl)=C1 NIDOTDANGJJHPU-UHFFFAOYSA-N 0.000 description 1
- LFIOFZKZCDMGFG-UHFFFAOYSA-N 4-amino-3-chlorobenzenesulfonamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1Cl LFIOFZKZCDMGFG-UHFFFAOYSA-N 0.000 description 1
- JGHDVROWMPBQSR-UHFFFAOYSA-N 4-chloro-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC=C(S(=O)(=O)N=C=O)C=C1 JGHDVROWMPBQSR-UHFFFAOYSA-N 0.000 description 1
- RUQAPQLDPWSAQM-UHFFFAOYSA-N 4-ethyl-2-nitroaniline Chemical compound CCC1=CC=C(N)C([N+]([O-])=O)=C1 RUQAPQLDPWSAQM-UHFFFAOYSA-N 0.000 description 1
- PUGDHSSOXPHLPT-UHFFFAOYSA-N 4-fluoro-2-nitroaniline Chemical compound NC1=CC=C(F)C=C1[N+]([O-])=O PUGDHSSOXPHLPT-UHFFFAOYSA-N 0.000 description 1
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 1
- DTJVECUKADWGMO-UHFFFAOYSA-N 4-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1 DTJVECUKADWGMO-UHFFFAOYSA-N 0.000 description 1
- VLJQDHDVZJXNQL-UHFFFAOYSA-N 4-methyl-n-(oxomethylidene)benzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)N=C=O)C=C1 VLJQDHDVZJXNQL-UHFFFAOYSA-N 0.000 description 1
- WHNVTBXYAOFNRP-UHFFFAOYSA-N 5,7-dichloro-4-phenylmethoxyquinoline-2-carboxylic acid Chemical compound C=12C(Cl)=CC(Cl)=CC2=NC(C(=O)O)=CC=1OCC1=CC=CC=C1 WHNVTBXYAOFNRP-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 206010049612 Autonomic seizure Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- WRWPPGUCZBJXKX-UHFFFAOYSA-N Cc(cc1)ccc1F Chemical compound Cc(cc1)ccc1F WRWPPGUCZBJXKX-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- 238000011767 DBA/2J (JAX™ mouse strain) Methods 0.000 description 1
- 206010013647 Drowning Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229940127337 Glycine Antagonists Drugs 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 238000012773 Laboratory assay Methods 0.000 description 1
- 208000001393 Lathyrism Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010034759 Petit mal epilepsy Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000037012 Psychomotor seizures Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229940116731 Uricosuric agent Drugs 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical class [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N c1ccccc1 Chemical compound c1ccccc1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 231100000858 damage to nervous tissue Toxicity 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229940080861 demerol Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- STRNXFOUBFLVIN-UHFFFAOYSA-N diethyl but-2-ynedioate Chemical compound CCOC(=O)C#CC(=O)OCC STRNXFOUBFLVIN-UHFFFAOYSA-N 0.000 description 1
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical class C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 1
- 210000003140 lateral ventricle Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WMGFMWONNPZDFY-UHFFFAOYSA-N methyl 4-[(4-methylphenyl)sulfonylamino]quinoline-2-carboxylate Chemical compound C12=CC=CC=C2NC(C(=O)OC)=CC1=NS(=O)(=O)C1=CC=C(C)C=C1 WMGFMWONNPZDFY-UHFFFAOYSA-N 0.000 description 1
- ZARPFUJQRZHAPE-UHFFFAOYSA-N methyl 5,7-dichloro-4-[(4-methylphenyl)sulfonylamino]quinoline-2-carboxylate Chemical compound C12=C(Cl)C=C(Cl)C=C2NC(C(=O)OC)=CC1=NS(=O)(=O)C1=CC=C(C)C=C1 ZARPFUJQRZHAPE-UHFFFAOYSA-N 0.000 description 1
- DNQDFGYHUHRIHR-UHFFFAOYSA-N methyl 5,7-dichloro-4-oxo-1h-quinoline-2-carboxylate Chemical compound ClC1=CC(Cl)=CC2=NC(C(=O)OC)=CC(O)=C21 DNQDFGYHUHRIHR-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000001095 motoneuron effect Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000004084 narcotic analgesic agent Substances 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 239000003383 uricosuric agent Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the present invention is directed to a new class of excitatory amino acid antagonists.
- Another aspect of the invention is directed to methods for the treatment of epilepsy, neurodegenerative diseases such as Huntington's disease, and for preventing ischemic/hypoxic damage to nervous tissues contained within the central nervous system.
- a further aspect of the invention is directed towards pharmaceutical formulations containing these excitatory amino acid antagonists.
- European Patent Application 0 386 839 discloses a class of 1,2,3,4-tetrahydroquinolines having an acidic substituent at the 2-position and at least one substituent at the 4-position. These compounds are glycine antagonists, inhibiting the effects of excitatory amino acids upon the NMDA receptor complex. They are useful in the treatment of a variety of neurodegenerative diseases.
- European Patent Application 0 303 387 discloses a class of 4-Oxo-1,4-dihydroquinolines having an acidic functionality at the 2-position. These compounds are NMDA antagonists and can be utilized in the treatment of neurodegenerative disorders.
- Harrison et al disclose a class of quinoline derivatives that are active as NMDA antagonists. These quinoline derivatives have an acidic function at the 2-position of the quinoline nucleus. Incorporation of a terminal acidic function at the 4-position of the quinoline ring increases the compounds affinity and selectivity for the glycine binding site of the NMDA receptor complex. These compounds are also useful in the treatment of neurodegenerative diseases.
- D is represented by C(O)OR1 or C(O)NR1R2;
- R1 and R2 are each independently represented by hydrogen or C1-C6 alkyl;
- Z is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3 and CF3;
- X is represented by one of the following substituents: -(CY2) n CY3 , -(CT2) n CT3 in which Y is represented by Cl;
- T is represented by F;
- n is represented by an integer from 0-3;
- A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3 or CF3;
- B is represented by one substituent selected from the group consisting of hydrogen, C(O)OR 1, C(O)NR1
- the two compounds encompassed by the first proviso above ie. methyl 4-( p -toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate and methyl 5,7-dichloro-4-(p-toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate (named 5,7-dichloro-4-[(4-methyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester in the present application) are active as excitatory amino acid antagonists. They have been described as intermediates in European Application 0 398 283.
- pharmaceutically acceptable acid addition salts is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
- inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
- organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids.
- Such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
- Such salts can exist in either a hydrated or substantially anhydrous form.
- the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
- compositions represented by Formula I are intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I or any of its intermediates.
- Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds.
- the quinoline nucleus may be optionally substituted.
- the quinoline nucleus is always substituted at the 2-position with either a carboxylic acid or a derivative thereof and at the 4-position with the sulfonimide depicted.
- Positions 3, 5, 6, 7, or 8 may be optionally substituted with tne substituents encompassed by Z.
- Z may represent up to 3 non-hydrogen substituents. These non-hydrogen substituents may be the same or different.
- X may be represented by a phenyl ring. When X is a phenyl ring, it may be optionally substituted as is indicated by the A and B substituents.
- A may be represented by up to 3 non-hydrogen substituents when B is hydrogen These substituents may be the same or different. They may be located at any of the ortho, meta, or para positions. B may only be represented by one non-hydrogen substituent. It may be located at any of the ortho, meta, or para positions. When B is not hydrogen, then up to 2 A substituents may also be present on the phenyl ring.
- X may also be represented by a thiophene ring.
- the thiophene ring may also be optionally substituted as indicated by the A substituent.
- A may represent up to 2 non-hydrogen substituents which may be the same or different. These non-hydrogen substituents may be bonded to positions 2, 4, 5 of a 3-thiophene ring or 3, 4, 5 of a 2-thiophene ring.
- A is a phenyl substituent and more preferably 4-aminophenyl and for Z to be a 5,7-dihalogen and more preferably 5,7-dichloro,5,7-dibromo, 5-bromo-7-chloro and 5-bromo-7-fluoro.
- Examples of compounds encompassed by the present invention include:
- the compounds of Formula I are excitatory amino acid antagonists. They antagonize the effects which excitatory amino acids have upon the NMDA receptor complex. They preferentially bind to the strychnine-insensitive glycine binding site associated with the NMDA receptor complex. They are useful in the treatment of a number of disease states.
- the compounds exhibit anti-convulsant properties and are useful in the treatment of epilepsy. They are useful in the treatment of grand mal seizures, petit mal seizures, psychomotor seizures, autonomic seizures, etc.
- One method of demonstrating their anti-epileptic properties is by their ability to inhibit the seizures that are caused by the administration of quinolinic acid. This test can be conducted in the following manner.
- mice One group containing ten mice are administered 0.01 - 100 ⁇ g of test compound intracerebroventricularly in a volume of 5 microliters of saline.
- a second control group containing an equal number of mice are administered an equal volume of saline as a control.
- both groups are administered 7.7 micrograms of quinolinic acid intracerebroventricularly in a volume of 5 microliters of saline.
- the animals are observed for 15 minutes thereafter for signs of clonic-tonic seizures.
- the control group will have a statistically higher rate of clonic-tonic seizures than will the test group.
- Another method of demonstrating the anti-epileptic properties of these compounds is by their ability to inhibit audiogenic convulsions in DBA/2 mice.
- This test can be conducted in the following manner. Typically one group of from 6-8 male DBA/2J audiogenic susceptible mice are administered from about 0.01 ⁇ g to about 100 ⁇ g of the test compound. The test compound is administered intracerebrally into the lateral ventricle of the brain. A second group of mice are administered an equal volume of saline control by the same route. Five minutes later the mice are placed individually in glass jars and are exposed to a sound stimulus of 110 decibels for 30 seconds. Each mouse is observed during the sound exposure for signs of seizure activity. The control group will have a statistically higher incidence of seizures than the group which receives the test compound.
- the compounds of Formula I are useful for preventing or minimizing the damage which nervous tissues contained within the CNS suffer upon exposure to either ischemic, hypoxic, or hypoglycemic conditions or as the result of physical trauma.
- Representative examples of such conditions include strokes or cerebrovascular accidents, hyperinsulinemia, cardiac arrest, physical trauma, drownings, suffocation, and neonatal anoxic trauma.
- the compounds should be administered to the patient within 24 hours of the onset of the hypoxic, ischemic, or hypoglycemic condition in order for the compounds to effectively minimize the CNS damage which the patient will experience.
- the compounds are also useful in the treatment of neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, senile dementia, glutaric acidaemia type I, Parkinson's disease, multi-infarct dementia, Lathyrism, amyotrophic lateral sclerosis, olivoponto cerebellar atrophy, motoneurone disease and neuronal damage associated with uncontrolled seizures.
- neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, senile dementia, glutaric acidaemia type I, Parkinson's disease, multi-infarct dementia, Lathyrism, amyotrophic lateral sclerosis, olivoponto cerebellar atrophy, motoneurone disease and neuronal damage associated with uncontrolled seizures.
- the administration of these compounds to a patient experiencing such a condition will serve to either prevent the patient from experiencing further neurodegeneration or it will decrease the rate at which the neurodegeneration occurs.
- the compounds will not correct any CNS damage that has already occurred as the result of either disease, or a lack of oxygen or sugar.
- the term “treat” refers to the ability of the compounds to prevent further damage or delay the rate at which any further damage occurs.
- the compounds are also useful for treating musculoskeletal disorders of neurenal origin such as spasticity or myoclonus.
- the compounds exhibit an anxiolytic effect and are thus useful in the treatment of anxiety. These anxiolytic properties can be demonstrated by their ability to block distress vocalizations in rat pups. This test is based upon the phenomenon that when a rat pup is removed from its litter, it will emit an ultrasonic vocalization. It was discovered that anxiolytic agents block these vocalizations. The testing methods have been described by Gardner, C.R., Distress vocalization in rat pups: a simple screening method for anxiolytic drugs. J. Pharmacol. Methods , 14:181-187 (1985) and Hans et al. Rat pup ultrasonic isolation calls: Possible mediation by the benzodiazepine receptor complex. Pharmacol. Biochem. Behav ., 24: 1263-1267 (1986).
- the compounds also exhibit an analgesic effect and are useful in controlling pain.
- the compounds may also be co-administered with a narcotic analgesic such as morphine, demerol, etc. When co-administered, the compounds decrease the rate at which patients develop tolerance to the pharmacological effects of these narcotics. It is also believed that this co-administration will help to prevent the patient from becoming addicted to the narcotic.
- the compounds are also effective in the treatment of migraine.
- the compounds may be utilized either prophylactically to prevent the occurrence of a migraine or during a migraine episode to terminate the migraine symptoms.
- the compounds need to be administered in a quantity sufficient to inhibit the effect which the excitatory amino acids have upon the NMDA receptor complex.
- the dosage range at which these compounds exhibit this antagonistic effect can vary widely depending upon the particular disease being treated, the severity of the patient's disease, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc.
- the compounds exhibit their therapeutic effect at a dosage range of from about 0.1 mg/kg/day to about 50 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.
- probenecid will potentiate the therapeutic activity of the excitatory amino acid antagonists of the present invention.
- the compounds will exhibit their therapeutic effects at lower doses and for longer periods in patients who are concurrently receiving probenecid.
- the mechanism by which probenecid potentiates their effects is not fully understood, however it is believed that probenecid decreases the rate at which the compounds are removed from the central nervous system as well as decreasing the rate of excretion by the kidneys.
- Probenecid increases the effective concentration of these compounds in both the CNS and in the systemic circulation.
- Probenecid is known in the art. It is available commercially from Merck Sharp and Dohme under the tradename Benemid® as well as being available from numerous other sources. Probenecid is a uricosuric agent and is utilized in the treatment of gout. Probenecid is a renal tubular transport blocking agent and has been utilized to increase plasma levels of penicillin. The pharmacology of probenecid is described in detail in the 45th Edition of the Physicians Desk reference on page 1379. Probenecid is currently available commercially as tablets. The sodium salt of probenecid is readily water soluble and injectable dosage forms can be prepared from this salt using techniques well known to those skilled in the art.
- the compounds of the invention may be administered concurrently with probenecid in order to treat any of the diseases or conditions described above.
- the quantity of probenecid that is required to potentiate the therapeutic effects of the compounds can vary widely depending upon the particular compound being administered, the patient, and the presence of other underlying disease states within the patient, etc.
- the probenecid may be administered at a dosage of from 0.5-3g/day. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.
- the probenecid will typically be administered from 2-4 times daily.
- the dosage range for the excitatory amino antagonists may be adjusted lower by a factor of from 2-10.
- the compounds of Formula I may be administered at the same dosage range in order to obtain an enhanced effect due to the higher therapeutic concentrations obtained.
- the compounds of the present invention may be administered by a variety of routes. They are effective if administered orally.
- the compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally).
- compositions can be manufactured utilizing techniques known in the art. Typically an antagonistic amount of the compound will be admixed with a pharmaceutically acceptable carrier.
- the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions.
- Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
- the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.
- binders such as acacia, cornstarch, or gelatin
- disintegrating agents such as potato starch or alginic acid
- a lubricant such as stearic acid or magnesium stearate.
- Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
- the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension.
- suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin.
- the pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art.
- the compounds When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid as is known in the art.
- the compounds of Formula I and the probenecid can be administered as two different pharmaceutical dosage forms. Alternatively, in order to increase patient convenience, the compounds and the probenecid may be compounded into a single pharmaceutical dosage form. These pharmaceutical compositions can be manufactured utilizing techniques known in the art similar to those described above. Typically an antagonistic amount of the compound of Formula I and an effective amount of probenecid will be admixed with a pharmaceutically acceptable carrier.
- the compounds of Formula I may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art.
- Neurodegenerative diseases are typically associated with a loss of NMDA receptors.
- the compounds of Formula I may be utilized in diagnostic procedures to aid physicians with the diagnosis of neurodegenerative diseases.
- the compounds may be labeled with imaging agents known in the art such as isotopic atoms and administered to a patient in order to determine whether the patient is exhibiting a decreased number of NMDA receptors and the rate at which that loss is occurring.
- X is a group represented by -(CY2) n CY3, -(CT2) n CT3, a phenyl derivative, a 2-thiophene derivative or a 3-thiophene derivative
- A is a group represented hydrogen, halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3 or CF3
- B is a group represented by hydrogen
- D is represented by C(O)OR1 or C(O)NR1R2, wherein R1 and R2 are as previously defined may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art.
- Scheme A provides a general synthetic scheme for preparing compounds of Formula I wherein X is a group represented by -(CY2) n CY3, -(CT2) n CT3, a phenyl derivative, a 2-thiophene derivative or a 3-thiophene derivative, A is a group represented hydrogen, halogen, OH, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3 or CF3 and B is a group represented by hydrogen, C(O)OR1 or C(O)NR1R2 wherein R1 and R2 are as previously defined and D is represented by C(O)OR1 or C(O)NR1R2.
- step a the appropriate sulfonyl chloride of structure (1) is amidated with ammonium hydroxide (2) to give the corresponding sulfonamide of structure (3).
- the appropriate sulfonyl chloride of structure (1) is contacted with a molar excess of ammonium hydroxide (2).
- the reactants are typically stirred together at room temperature for a period of time ranging from 10-24 hours.
- the sulfonamide of structure (3) is recovered from the reaction zone by evaporation of the volatiles, optional acidification with a suitable acid such as hydrochloric acid, followed by filtration.
- step b the appropriate sulfonamide of structure (3) is acylated with either oxalyl chloride, phosgene or triphosgene, oxalyl chloride being preferred, to give the corresponding N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4).
- the appropriate sulfonamide of structure (3) is contacted with a molar excess of oxalyl chloride, phosgene or triphosgene.
- the reactants are typically stirred together at a temperature range of from room temperature to reflux and for a period of time ranging from 5-24 hours.
- the N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4) is recovered from the reaction zone by evaporation of the volatiles.
- step c the appropriate N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4) is converted to the corresponding sulfonyl isocyanate of structure (5).
- the appropriate N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4) is contacted with an appropriate anhydrous organic solvent such as o-dichlorobenzene.
- the reactants are typically stirred together at reflux temperature for a period of time ranging from 5-24 hours.
- the sulfonyl isocyanate of structure (5) is recovered from the reaction zone by fractional distillation.
- the appropriate sulfonamide of structure (3) can be converted to the corresponding sulfonyl isocyanate of structure (5) by combining step b and step c and using a catalytic amount of a C1-C4 alkyl or phenyl isocyanate according to the procedure cited in J.Org.Chem 31 2658-61 1966 .
- step d the appropriate sulfonyl isocyanate of structure (5) is reacted with an appropriate 4-oxo-1,4-dihydroquinoline of structure (6) to give the appropriate 4-sulfonimide-1,4-dihydroquinoline of structure (7).
- the appropriate sulfonyl isocyanate of structure (5) is contacted with a slight molar deficiency of an appropriate 4-oxo-1,4-dihydroquinoline of structure (6).
- the reactants are typically contacted in a polar anhydrous organic solvent such as acetonitrile or propionitrile.
- the reactants are typically stirred together for a period of time ranging from 4-24 hours and at a temperature range of from room temperature to reflux.
- the 4-sulfonimide-1,4-dihydroquinoline of structure (7) is recovered from the reaction zone by filtration or other methods known in the art. It may be purified by recrystallization as is known in the art.
- step e the ester or amide functionality of the appropriate 4-sulfonimide-1,4-dihydroquinolines of structure (7) is hydrolyzed to give the corresponding 4-sulfonimide-1,4-dihydroquinoline-2-carboxylic acids of structure (8).
- the appropriate 4-sulfonimide-1,4-dihydroquinoline of structure (7) wherein D is a group represented by C(O)OR1 and R1 is a C1-C6 alkyl is contacted with a suitable base, such as lithium hydroxide or sodium hydroxide.
- a suitable base such as lithium hydroxide or sodium hydroxide.
- the reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux.
- the 4-sulfonimide-1,4-dihydroquinoline-2-carboxylic acid of structure (8) is recovered from the reaction zone by acidification followed by filtration.
- any protecting groups on A and/or B may be removed under the conditions of optional step e.
- Step b N-[(1-Oxo-2-oxo-2-chloro)ethyl]-4-(fluoro)benzenesulfonamide
- Step b N-[(1-Oxo-2-oxo-2-chloro)ethyl]-(2-thiophene)sulfonamide
- Step b N-[(1-Oxo-2-oxo-2-chloro)ethyl]-4-(methoxy)benzenesulfonamide
- Scheme B provides a general synthetic scheme for preparing the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF 3, B is a group represented NH(CO)OR3 and D is represented by C(O)OR1, wherein R1 is C1-C6 alkyl or C(O)NR1R2 wherein R1 and R2 are as previously defined, the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF 3, B is a group represented NHC(O)R3, NH(CO)OR3, NHC(O)NHR3, NHSO2CF3, or NHSO2C6
- step a the appropriate aminobenzenesulfonyl chloride of structure (9) is amidated with ammonium hydroxide (2) to give the corresponding aminobenzene sulfonamide of structure (10) as described previously in Scheme A, step a.
- step b both sulfonamide and amino functionalities of the appropriate aminobenzene sulfonamide of structure (10) are converted to the corresponding (isocyanato)benzenesulfonyl isocyanate of structure (11).
- the appropriate aminobenzenesulfonamide of structure (10) is contacted with a molar excess of either phosgene, triphosgene or oxalyl chloride, phosgene being preferred.
- the reactants are typically contacted in a suitable organic solvent such as nitrobenzene.
- the reactants are typically stirred together at a temperature range of from -10°C to reflux and for a period of time ranging from 5-24 hours.
- the (isocyanato)benzenesulfonyl isocyanate of structure (11) is recovered from the reaction zone by evaporation of the volatiles.
- step c the appropriate (isocyanato)benzenesulfonyl isocyanate of structure (11) is first reacted with an appropriate 4-oxo-1,4-dihydroquinoline of structure (6) to give the intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline.
- the isocyanato functionality of the intermediate 4-(isocyanato)benzene)sulfonimide-1,4-dihydroquinoline is then decomposed by the addition of an appropriate alcohol of the formula R3OH to give the corresponding 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline of structure (12).
- the appropriate (isocyanato)benzenesulfonyl isocyanate of structure (11) is contacted with a slight molar deficiency of an appropriate 4-oxo-1,4-dihydroquinoline of structure (6).
- the reactants are typically contacted in a polar anhydrous organic solvent such as acetonitrile or propionitrile.
- the reactants are typically stirred together for a period of time ranging from 4-24 hours and at a temperature range of from room temperature to reflux.
- the intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline is recovered from the reaction zone by filtration.
- the intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline is then treated with a molar excess of the appropriate alcohol of the formula R3OH.
- the reactants are typically stirred together at reflux temperature for a period of time ranging from 2-24 hours.
- the 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline of structure (12) is recovered from the reaction zone by filtration. It may be purified by recrystallization as is known in the art.
- the isocyanato functionality of the appropriate intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline may be decomposed by the addition of an appropriate amine of the formula H2NR3 to give the corresponding 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- both the carbamoyl functionality and the ester or amide functionality of the appropriate 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline of structure (12) are hydrolyzed with a base such as sodium hydroxide to give the corresponding 4-[(amino)benzenesulfonimide)-1,4-dihydroquinoline-2-carboxylic acid of structure (13) as described previously in Scheme A, optional step e.
- the 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (13) wherein A is a group represented by C(O)OR1 wherein R1 is C1-C4 alkyl, or C(O)NR1R2 can be prepared as described later in Scheme D, step a and optional step b1 or optional step b2.
- step e the amino functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) can be functionalized to give either the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14), 4-[(ureido)benzenesulfonimide]-l,4-dihydroquinoline of structure (14), 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) or 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) can be acylated to give the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- the appropriate 4-[(amino)benzenesulfonimide-]-1,4-dihydroquinoline of structure (13) is contacted with a molar equivalent of the appropriate acylating agent represented by the formula R3COCl.
- the reactants are typically contacted in a suitable non-nucleophilic organic base such as pyridine or an aqueous solvent such as dioxane/water buffered to pH 10 with a base such as sodium hydroxide.
- the reactants are typically stirred together at room temperature for a period of time ranging from 2-24 hours.
- the 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) is recovered from the reaction zone by extractive methods as is known in the art.
- the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) is contacted with a molar equivalent of the appropriate isocyante of the formula R3NCO.
- the reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran.
- the reactants are typically stirred together at room temperature for a period of time ranging from 1-5 hours.
- the 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) is recovered from the reaction zone by extractive methods as is known in the art.
- the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) is contacted with a molar excess of trifluoromethanesulfonic anhydride, and a molar excess of a base such as diisopropylethylamine.
- the reactants are typically contacted in methylene chloride.
- the reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from -78°C to 85°C.
- the 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) is recovered from the reaction zone by extractive methods as is known in the art. Similarly, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) is converted to the corresponding 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) using benzenesulfonyl chloride instead of trifluoromethanesulfonic anhydride.
- Scheme C provides a general synthetic procedure for preparing the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF3, B is a group represented by NH(CO)OR3 and D is represented by C(O)OR1, wherein R1 is hydrogen.
- the appropriate 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (15) is contacted with a molar excess of an appropriate base such as lithium hydroxide.
- the reactants are typically contacted in a suitable solvent mixture such as methanol/water.
- the reactants are typically stirred together at room temperature for a period of time ranging from 2-10 hours.
- the 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (16) is recovered from the reaction zone by extractive methods as is known in the art.
- A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF3,
- B is a group represented NH2, NHC(O)R3, NHC(O)NHR3, NHSO2CF3, or NHSO2C6H5
- D is represented by C(O)OR1, wherein R1 is C1-C6 alkyl or C(O)NR1R2 may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art.
- a general synthetic procedure for preparing these compounds is set forth in Scheme D. In Scheme D, all substituents unless otherwise indicated are as previously defined.
- B' NHC(O)R3, NHC(O)NHR3, NHSO2CF3 or NHSO2C6H5
- R1' C1-C6 alkyl
- Scheme D provides a general synthetic scheme for preparing compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF3, B is a group represented NH2, NBC(O)R3, NHC(O)NHR3, NHSO2CF3, or NHSO2C6H5 and D is represented by C(O)OR1, wherein R1 is C1-C6 alkyl, or C(O)NR1R2.
- step a the carboxylic acid functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (13) is esterified to give the corresponding 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17).
- the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (13) is contacted with a molar excess of methanolic hydrochloric acid.
- the reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to 60°C.
- the 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is recovered from the reaction zone by extractive methods as is known in the art.
- step b1 the methyl ester functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is amidated to give the corresponding 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, carboxyamide of structure (18).
- the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is contacted with a molar equivalent of an appropriate amine of the formula NHR1R2 and a catalytic amount of a amidation catalyst such as 2-hydroxypyridine or potassium cyanide.
- the reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux.
- the 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (18) is recovered from the reaction zone by extractive methods as is known in the art.
- step b2 the methyl ester functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is transesterified to give the corresponding 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (19).
- the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is contacted with a molar excess of an appropriate alcohol of the formula R1OH and a catalytic amount of an acid such as concentrated sulfuric acid.
- the reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux.
- the 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (19) is recovered from the reaction zone by extractive methods as is known in the art.
- step c1 the amine functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (18) can be functionalized to give either the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20), 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20), 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20) or 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20) as described previously in Scheme B, optional step e.
- step c2 the amine functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (19) can be functionalized to give the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21), 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21), 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21) or 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21) as described previously in Scheme B, optional step e.
- Scheme E provides a general synthetic scheme for preparing compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF3, B is a group represented by NR1R2 and D is represented by C(O)OR1 wherein R1 is hydrogen.
- the appropriate 4-[fluorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (22) is contacted with an excess amount of an appropriate amine of structure (23).
- the reactants are typically contacted in a suitable polar organic solvent, such as dimethyl sulfoxide.
- the reactants are typically stirred together for a period of time ranging from 4-10 hours and at a temperature range of from 50-95°C.
- the 4-[dialkylaminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (24) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by silica gel chromatography.
- the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF3, B is a group represented by NR1R2 and D is represented by C(O)OR1, wherein R1 is C1-C6 alkyl, or C(O)NR1R2 may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme F. In Scheme F all substituents, unless otherwise indicated are as previously defined. R1' C1-C6 alkyl
- Scheme F provides a general synthetic scheme for preparing compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, OCF3, CF3, B is a group represented by NR1R2 and D is represented by C(O)OR1, wherein R1 is C1-C6 alkyl, or C(O)NR1R2.
- step a the carboxylic acid functionality of the appropriate 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (24) is esterified to give the corresponding 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (25) as described previously in Scheme D, step a.
- step b1 the methyl ester functionality of the appropriate 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (25) is amidated to give the corresponding 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxamide of structure (26) as described previously in Scheme E, optional step b1.
- step b2 the methyl ester functionality of the appropriate 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (25) is transesterified to give the corresponding 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (27) as described previously in Scheme D, optional step b2.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Neurosurgery (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
- This is a continuation in part of U.S. Serial No. 07/700,004, filed 05/14/91, which is a continuation in part of U.S. Serial No. 07/661,780, filed 02/27/91, now pending.
- The present invention is directed to a new class of excitatory amino acid antagonists. Another aspect of the invention is directed to methods for the treatment of epilepsy, neurodegenerative diseases such as Huntington's disease, and for preventing ischemic/hypoxic damage to nervous tissues contained within the central nervous system. A further aspect of the invention is directed towards pharmaceutical formulations containing these excitatory amino acid antagonists.
-
- European Patent Application 0 386 839 discloses a class of 1,2,3,4-tetrahydroquinolines having an acidic substituent at the 2-position and at least one substituent at the 4-position. These compounds are glycine antagonists, inhibiting the effects of excitatory amino acids upon the NMDA receptor complex. They are useful in the treatment of a variety of neurodegenerative diseases.
- European Patent Application 0 303 387 discloses a class of 4-Oxo-1,4-dihydroquinolines having an acidic functionality at the 2-position. These compounds are NMDA antagonists and can be utilized in the treatment of neurodegenerative disorders.
- Harrison et al disclose a class of quinoline derivatives that are active as NMDA antagonists. These quinoline derivatives have an acidic function at the 2-position of the quinoline nucleus. Incorporation of a terminal acidic function at the 4-position of the quinoline ring increases the compounds affinity and selectivity for the glycine binding site of the NMDA receptor complex. These compounds are also useful in the treatment of neurodegenerative diseases. in which D is represented by C(O)OR₁ or C(O)NR₁R₂; R₁ and R₂, are each independently represented by hydrogen or C₁-C₆ alkyl; Z is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl,
C₁-C₆ alkoxy, OCF₃ and CF₃; X is represented by one of the following substituents:
-(CY₂)nCY₃ , -(CT₂)nCT₃
- The two compounds encompassed by the first proviso above (ie. methyl 4-(p-toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate and methyl 5,7-dichloro-4-(p-toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate (named 5,7-dichloro-4-[(4-methyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester in the present application) are active as excitatory amino acid antagonists. They have been described as intermediates in European Application 0 398 283. Those compounds encompassed by the second proviso where disclosed by Wright, in Synthesis, 1984, 1058. They are also active as excitatory amino acid antagonists. The compounds encompassed by these two provisos should be considered within the scope of any method, use, or formulation claim.
- As used in this application:
- a) the term "halogen" refers to a fluorine, chlorine, or bromine atom;
- b) the terms "lower alkyl group and C₁₋₆ alkyl" refer to a branched or straight chained alkyl group containing from 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, etc;
- c) the terms "lower alkoxy group and C₁₋₆ alkoxy" refer to a straight or branched alkoxy group containing from 1-6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentoxy, n-hexoxy, etc;
- d) the term "phenyl derivative" refers to:
- e) the term "2-thiophene derivative" refers to:
- f) the term "3-thiophene derivative" refers to:
- g) the term "pharmaceutically acceptable salts thereof" refers to either an acid addition salt or a basic addition salt;
- h) the term "C₆H₅" refers to an unsubstituted phenyl ring.
- The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
- The expression "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds.
-
- As is indicated by the Z substituent, the quinoline nucleus may be optionally substituted. The quinoline nucleus is always substituted at the 2-position with either a carboxylic acid or a derivative thereof and at the 4-position with the sulfonimide depicted. Positions 3, 5, 6, 7, or 8 may be optionally substituted with tne substituents encompassed by Z. Z may represent up to 3 non-hydrogen substituents. These non-hydrogen substituents may be the same or different.
- X may be represented by a phenyl ring. When X is a phenyl ring, it may be optionally substituted as is indicated by the A and B substituents. A may be represented by up to 3 non-hydrogen substituents when B is hydrogen These substituents may be the same or different. They may be located at any of the ortho, meta, or para positions. B may only be represented by one non-hydrogen substituent. It may be located at any of the ortho, meta, or para positions. When B is not hydrogen, then up to 2 A substituents may also be present on the phenyl ring.
- X may also be represented by a thiophene ring. The thiophene ring may also be optionally substituted as indicated by the A substituent. A may represent up to 2 non-hydrogen substituents which may be the same or different. These non-hydrogen substituents may be bonded to positions 2, 4, 5 of a 3-thiophene ring or 3, 4, 5 of a 2-thiophene ring.
- It is currently preferred for A to be a phenyl substituent and more preferably 4-aminophenyl and for Z to be a 5,7-dihalogen and more preferably 5,7-dichloro,5,7-dibromo, 5-bromo-7-chloro and 5-bromo-7-fluoro.
- Examples of compounds encompassed by the present invention include:
- 5,7-Dichloro-4-[4-(trifluoromethyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[4-(trifluoromethyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[4-(fluoro)benzenesulfonimide]-1,4-dihydroquinolone-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[4-(fluoro)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[(2-thiophene)sulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[(2-thiophene)sulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[4-(methoxy)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dich1oro-4-[4-(methoxy)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[(4-methyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[(4-methyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[(4-chloro)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[(4-chloro)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[trifluoromethylsulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[trifluoromethylsulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[2-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[2-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[4-(methylcarbamoyl)-3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[4-amino-3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[4-(methylcarbamoyl)-2-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-Dichloro-4-[4-amino-2-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid.
- The compounds of Formula I are excitatory amino acid antagonists. They antagonize the effects which excitatory amino acids have upon the NMDA receptor complex. They preferentially bind to the strychnine-insensitive glycine binding site associated with the NMDA receptor complex. They are useful in the treatment of a number of disease states.
- The compounds exhibit anti-convulsant properties and are useful in the treatment of epilepsy. They are useful in the treatment of grand mal seizures, petit mal seizures, psychomotor seizures, autonomic seizures, etc. One method of demonstrating their anti-epileptic properties is by their ability to inhibit the seizures that are caused by the administration of quinolinic acid. This test can be conducted in the following manner.
- One group containing ten mice are administered 0.01 - 100 µg of test compound intracerebroventricularly in a volume of 5 microliters of saline. A second control group containing an equal number of mice are administered an equal volume of saline as a control. Approximately 5 minutes later, both groups are administered 7.7 micrograms of quinolinic acid intracerebroventricularly in a volume of 5 microliters of saline. The animals are observed for 15 minutes thereafter for signs of clonic-tonic seizures. The control group will have a statistically higher rate of clonic-tonic seizures than will the test group.
- Another method of demonstrating the anti-epileptic properties of these compounds is by their ability to inhibit audiogenic convulsions in DBA/2 mice. This test can be conducted in the following manner. Typically one group of from 6-8 male DBA/2J audiogenic susceptible mice are administered from about 0.01 µg to about 100 µg of the test compound. The test compound is administered intracerebrally into the lateral ventricle of the brain. A second group of mice are administered an equal volume of saline control by the same route. Five minutes later the mice are placed individually in glass jars and are exposed to a sound stimulus of 110 decibels for 30 seconds. Each mouse is observed during the sound exposure for signs of seizure activity. The control group will have a statistically higher incidence of seizures than the group which receives the test compound.
- The compounds of Formula I are useful for preventing or minimizing the damage which nervous tissues contained within the CNS suffer upon exposure to either ischemic, hypoxic, or hypoglycemic conditions or as the result of physical trauma. Representative examples of such conditions include strokes or cerebrovascular accidents, hyperinsulinemia, cardiac arrest, physical trauma, drownings, suffocation, and neonatal anoxic trauma. The compounds should be administered to the patient within 24 hours of the onset of the hypoxic, ischemic, or hypoglycemic condition in order for the compounds to effectively minimize the CNS damage which the patient will experience.
- The compounds are also useful in the treatment of neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, senile dementia, glutaric acidaemia type I, Parkinson's disease, multi-infarct dementia, Lathyrism, amyotrophic lateral sclerosis, olivoponto cerebellar atrophy, motoneurone disease and neuronal damage associated with uncontrolled seizures. The administration of these compounds to a patient experiencing such a condition will serve to either prevent the patient from experiencing further neurodegeneration or it will decrease the rate at which the neurodegeneration occurs.
- As is apparent to those skilled in the art, the compounds will not correct any CNS damage that has already occurred as the result of either disease, or a lack of oxygen or sugar. As used in this application, the term "treat" refers to the ability of the compounds to prevent further damage or delay the rate at which any further damage occurs. The compounds are also useful for treating musculoskeletal disorders of neurenal origin such as spasticity or myoclonus.
- The compounds exhibit an anxiolytic effect and are thus useful in the treatment of anxiety. These anxiolytic properties can be demonstrated by their ability to block distress vocalizations in rat pups. This test is based upon the phenomenon that when a rat pup is removed from its litter, it will emit an ultrasonic vocalization. It was discovered that anxiolytic agents block these vocalizations. The testing methods have been described by Gardner, C.R., Distress vocalization in rat pups: a simple screening method for anxiolytic drugs. J. Pharmacol. Methods, 14:181-187 (1985) and Insel et al. Rat pup ultrasonic isolation calls: Possible mediation by the benzodiazepine receptor complex. Pharmacol. Biochem. Behav ., 24: 1263-1267 (1986).
- The compounds also exhibit an analgesic effect and are useful in controlling pain. The compounds may also be co-administered with a narcotic analgesic such as morphine, demerol, etc. When co-administered, the compounds decrease the rate at which patients develop tolerance to the pharmacological effects of these narcotics. It is also believed that this co-administration will help to prevent the patient from becoming addicted to the narcotic. The compounds are also effective in the treatment of migraine. The compounds may be utilized either prophylactically to prevent the occurrence of a migraine or during a migraine episode to terminate the migraine symptoms.
- In order to exhibit these therapeutic properties, the compounds need to be administered in a quantity sufficient to inhibit the effect which the excitatory amino acids have upon the NMDA receptor complex. The dosage range at which these compounds exhibit this antagonistic effect can vary widely depending upon the particular disease being treated, the severity of the patient's disease, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. Typically the compounds exhibit their therapeutic effect at a dosage range of from about 0.1 mg/kg/day to about 50 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.
- It has been discovered that probenecid will potentiate the therapeutic activity of the excitatory amino acid antagonists of the present invention. Thus the compounds will exhibit their therapeutic effects at lower doses and for longer periods in patients who are concurrently receiving probenecid. The mechanism by which probenecid potentiates their effects is not fully understood, however it is believed that probenecid decreases the rate at which the compounds are removed from the central nervous system as well as decreasing the rate of excretion by the kidneys. Probenecid increases the effective concentration of these compounds in both the CNS and in the systemic circulation.
- Probenecid is known in the art. It is available commercially from Merck Sharp and Dohme under the tradename Benemid® as well as being available from numerous other sources. Probenecid is a uricosuric agent and is utilized in the treatment of gout. Probenecid is a renal tubular transport blocking agent and has been utilized to increase plasma levels of penicillin. The pharmacology of probenecid is described in detail in the 45th Edition of the Physicians Desk reference on page 1379. Probenecid is currently available commercially as tablets. The sodium salt of probenecid is readily water soluble and injectable dosage forms can be prepared from this salt using techniques well known to those skilled in the art.
- The compounds of the invention may be administered concurrently with probenecid in order to treat any of the diseases or conditions described above. The quantity of probenecid that is required to potentiate the therapeutic effects of the compounds can vary widely depending upon the particular compound being administered, the patient, and the presence of other underlying disease states within the patient, etc. Typically though, the probenecid may be administered at a dosage of from 0.5-3g/day. Repetitive daily administration may be desirable and will vary according to the conditions outlined above. The probenecid will typically be administered from 2-4 times daily.
- With the concurrent administration of probenecid, the dosage range for the excitatory amino antagonists may be adjusted lower by a factor of from 2-10. Alternatively, the compounds of Formula I may be administered at the same dosage range in order to obtain an enhanced effect due to the higher therapeutic concentrations obtained.
- The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally).
- Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically an antagonistic amount of the compound will be admixed with a pharmaceutically acceptable carrier.
- For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
- In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
- For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art. When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid as is known in the art.
- The compounds of Formula I and the probenecid can be administered as two different pharmaceutical dosage forms. Alternatively, in order to increase patient convenience, the compounds and the probenecid may be compounded into a single pharmaceutical dosage form. These pharmaceutical compositions can be manufactured utilizing techniques known in the art similar to those described above. Typically an antagonistic amount of the compound of Formula I and an effective amount of probenecid will be admixed with a pharmaceutically acceptable carrier.
- As used in this application:
- a) the term "patient" refers to warm blooded animals such as, for example, guinea pigs, mice, rats, cats, rabbits, dogs, monkeys, chimpanzees, and humans;
- b) the term "treat" refers to the ability of the compounds to either relieve, alleviate, or slow the progression of the patient's disease or prophylactically prevent its occurrence or the manifestation of its symptoms;
- c) the term "neurodegeneration" refers to a progressive death and disappearance of a population of nerve cells occurring in a manner characteristic of a particular disease state and leading to brain damage;
- d) the phrase "concurrent administration" refers to administering the probenecid at an appropriate time so that it will potentiate the antagonistic effects of the compounds of Formula I. This may mean simultaneous administration or administration at appropriate but different times. Establishing such a proper dosing schedule will be readily apparent to one skilled in the art.
- The compounds of Formula I may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art.
- Neurodegenerative diseases are typically associated with a loss of NMDA receptors. Thus, the compounds of Formula I may be utilized in diagnostic procedures to aid physicians with the diagnosis of neurodegenerative diseases. The compounds may be labeled with imaging agents known in the art such as isotopic atoms and administered to a patient in order to determine whether the patient is exhibiting a decreased number of NMDA receptors and the rate at which that loss is occurring.
- The compounds of Formula I wherein X is a group represented by -(CY₂)nCY₃, -(CT₂)nCT₃, a phenyl derivative, a 2-thiophene derivative or a 3-thiophene derivative, A is a group represented hydrogen, halogen, OH, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃ or CF₃ and B is a group represented by hydrogen, C(O)OR₁ or C(O)NR₁R₂ and D is represented by C(O)OR₁ or C(O)NR₁R₂, wherein R₁ and R₂ are as previously defined may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme A. In Scheme A, all substituents unless otherwise indicated are as previously defined.
R₁' =C₁-C₆ alkyl
D' = C(O)OH - Scheme A provides a general synthetic scheme for preparing compounds of Formula I wherein X is a group represented by -(CY₂)nCY₃, -(CT₂)nCT₃, a phenyl derivative, a 2-thiophene derivative or a 3-thiophene derivative, A is a group represented hydrogen, halogen, OH, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃ or CF₃ and B is a group represented by hydrogen, C(O)OR₁ or C(O)NR₁R₂ wherein R₁ and R₂ are as previously defined and D is represented by C(O)OR₁ or C(O)NR₁R₂.
- In step a, the appropriate sulfonyl chloride of structure (1) is amidated with ammonium hydroxide (2) to give the corresponding sulfonamide of structure (3).
- For example, the appropriate sulfonyl chloride of structure (1) is contacted with a molar excess of ammonium hydroxide (2). The reactants are typically stirred together at room temperature for a period of time ranging from 10-24 hours. The sulfonamide of structure (3) is recovered from the reaction zone by evaporation of the volatiles, optional acidification with a suitable acid such as hydrochloric acid, followed by filtration.
- For those sulfonyl chlorides of structure (1) wherein A is a group represented by OH or B is represented by C(O)OR₁, wherein R₁ is hydrogen, it may be necessary to protect the appropriate functionality represented by A and/or B due to the conditions of the reaction sequence. The selection and utilization of appropriate protecting groups are well known to one of ordinary skill in the art and are described in "Protective Groups in Organic Synthesis", Theodora W. Greene, Wiley (1981).
- In step b, the appropriate sulfonamide of structure (3) is acylated with either oxalyl chloride, phosgene or triphosgene, oxalyl chloride being preferred, to give the corresponding N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4).
- For example, the appropriate sulfonamide of structure (3) is contacted with a molar excess of oxalyl chloride, phosgene or triphosgene. The reactants are typically stirred together at a temperature range of from room temperature to reflux and for a period of time ranging from 5-24 hours. The N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4) is recovered from the reaction zone by evaporation of the volatiles.
- In step c, the appropriate N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4) is converted to the corresponding sulfonyl isocyanate of structure (5).
- For example, the appropriate N-[(1-oxo-2-oxo-2-chloro)ethyl]-sulfonamide of structure (4) is contacted with an appropriate anhydrous organic solvent such as o-dichlorobenzene. The reactants are typically stirred together at reflux temperature for a period of time ranging from 5-24 hours. The sulfonyl isocyanate of structure (5) is recovered from the reaction zone by fractional distillation.
- Alternatively, the appropriate sulfonamide of structure (3) can be converted to the corresponding sulfonyl isocyanate of structure (5) by combining step b and step c and using a catalytic amount of a C₁-C₄ alkyl or phenyl isocyanate according to the procedure cited in J.Org.Chem 31 2658-61 1966.
- In step d, the appropriate sulfonyl isocyanate of structure (5) is reacted with an appropriate 4-oxo-1,4-dihydroquinoline of structure (6) to give the appropriate 4-sulfonimide-1,4-dihydroquinoline of structure (7).
- For example, the appropriate sulfonyl isocyanate of structure (5) is contacted with a slight molar deficiency of an appropriate 4-oxo-1,4-dihydroquinoline of structure (6). The reactants are typically contacted in a polar anhydrous organic solvent such as acetonitrile or propionitrile. The reactants are typically stirred together for a period of time ranging from 4-24 hours and at a temperature range of from room temperature to reflux. The 4-sulfonimide-1,4-dihydroquinoline of structure (7) is recovered from the reaction zone by filtration or other methods known in the art. It may be purified by recrystallization as is known in the art.
- In optional step e, the ester or amide functionality of the appropriate 4-sulfonimide-1,4-dihydroquinolines of structure (7) is hydrolyzed to give the corresponding 4-sulfonimide-1,4-dihydroquinoline-2-carboxylic acids of structure (8).
- For example, the appropriate 4-sulfonimide-1,4-dihydroquinoline of structure (7) wherein D is a group represented by C(O)OR₁ and R₁ is a C₁-C₆ alkyl is contacted with a suitable base, such as lithium hydroxide or sodium hydroxide. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux. The 4-sulfonimide-1,4-dihydroquinoline-2-carboxylic acid of structure (8) is recovered from the reaction zone by acidification followed by filtration.
- In addition, any protecting groups on A and/or B may be removed under the conditions of optional step e.
- Starting materials for use in the general synthetic procedures outlined in Scheme A are readily available to one of ordinary skill in the art. Certain 4-oxo-1,4-dihydroquinoline-2-carboxylic acids and amides and 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid and acid chloride are described in European Patent Application of Leeson, Publication #0 303 387, February 15, 1989 and trifluoromethylsulfonyl isocyanate is described in J.Fluorine Chemistry 4 83-98 1974 and certain sulfonamides of structure (3) are described in J.Org.Chem 31 2658-61 1966.
- The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; "mp" refers to melting point; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "µL" refers to microliters; "µg" refers to micrograms; and "µM" refers to micromolar.
-
- Combine 4-(trifluoromethyl)benzenesulfonyl chloride (2.5g, 0.01mol) and concentrated ammonium hydroxide (80mL). Seal and stir for 16 hours at room temperature. Heat at 90°C to remove the ammonia and then add hydrochloric acid (lmL of a 12N solution). Cool, filter and dry to give the title compound as an off-white solid (1.61g, 72%); mp 175-6°C.
- Anal. Calcd for C₇H₆F₃NO₂S: C, 37.33; H, 2.69; N, 6.22;
Found: C, 37.13; H, 2.45; N 6.13. - Combine 4-(trifluoromethyl)benzenesulfonamide (1.44g, 6.4mmol) and oxalyl chloride (15mL) and reflux for 9 hours. Evaporate the excess oxalyl chloride in vacuo to give the title compound.
- Combine N-[(1-oxo-2-oxo-2-chloro)ethyl]-4-(trifluoromethyl)benzenesulfonamide (2g, 6.4mmol) and o-dichlorobenzene (25mL). Reflux for 16 hours then remove the solvent by fractional distillation (6mm Hg vacuum through a column packed with glass helices). Purify by distillation to give the title compound (1.15g. 72%); bp 62-4°C @ 0.075mm.
- Combine [4-(trifluoromethyl)benzenesulfonyl]isocyanate (1.15g, 4.5mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.03g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound as a yellow solid (1.47g, 81%); mp 252-3°C (acetonitrile).
- Anal. Calcd for C₁₈H₁₁Cl₂F₃N₂O₄S: C, 45.11; H, 2.31; N, 5.85;
Found: C, 45.04; H, 2.23; N, 5.85. -
- Anal. Calcd for C₁₇H₉Cl₂F₃N₂O₄S: C, 43.89; H, 1.95; N. 6.02;
Found: C, 43.82; H, 1.76; N, 5.97. -
- Combine 4-(fluoro)benzenesulfonyl chloride (6g, 0.03mol) and concentrated ammonium hydroxide (80mL). Seal and stir for 16 hours at room temperature. Heat at 90°C to remove the ammonia and then add hydrochloric acid (1mL of a 12N solution). Cool, filter and dry to give the title compound as an off-white solid (4.4g, 85%); mp 124-5°C.
- Anal. Calcd for C₇H₆FNO₂S: C, 41.13; H, 3.45; N, 8;
Found: C, 41.19; H, 3.39; N. 7.92. - Combine 4-(fluoro)benzenesulfonamide (1.12g, 6.4mmol) and oxalyl chloride (15mL) and reflux for 9 hours. Evaporate the excess oxalyl chloride in vacuo to give the title compound.
- Combine N-[(1-oxo-2-oxo-2-chloro)ethyl]-4-(fluoro)benzenesulfonamide (1.70g, 6.4mmol) and o-dichlorobenzene (25mL). Reflux for 16 hours then remove the solvent by fractional distillation (6mm Hg vacuum through a column packed with glass helices). Purify by distillation to give the title compound (1.15g, 89%); bp 80°C @ 0.075mm.
- Combine [4-(fluoro)benzenesulfonyl]isocyanate (905mg, 4.5mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid methyl ester (1.03g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound as a yellow solid (1.56g, 83%); mp 234-5°C.
-
- Combine 5,7-dichloro-4-[4-(fluoro)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.21g, 2.9mmol), lithium hydroxide hydrate (245mg, 5.8mmol), water (6mL) and methanol (30mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter the light yellow solid, wash with water and dry to give the title compound (457mg, 39%); mp 225.5-223°C (dec).
- Anal. Calcd for C₁₆H₉Cl₂FN₂O₄S.1.1H₂O: C, 44.17; H, 2.60; N, 6.44;
Found: C, 44.26; H. 2.41; N, 5.20. -
- Combine 2-thiophenesulfonyl chloride (5g, 0.01mol) and concentrated ammonium hydroxide (80mL). Seal and stir for 16 hours at room temperature. Heat at 90°C to remove the ammonia and then add hydrochloric acid (1mL of a 12N solution). Cool, filter and dry to give the title compound as an off-white solid (4g, 90%); mp 137-8°C.
- Anal. Calcd for C₄H₅NO₂S₂: C, 29.43; H, 3.09; N, 8.58;
Found: C, 29.34; H, 2.97; N. 8.52. - Combine (2-thiophene)sulfonamide (1.04g, 6.4mmol) and oxalyl chloride (15mL) and reflux for 9 hours. Evaporate the excess oxalyl chloride in vacuo to give the title compound.
- Combine N-[(1-oxo-2-oxo-2-chloro)ethyl]-(2-thiophene)sulfonamide (1.63g, 6.4mmol) and o-dichlorobenzene (25mL). Reflux for 16 hours then remove the solvent by distillation (6mm Hg vacuum through a column packed with glass helices). Purify by distillation to give the title compound (680mg, 30%); bp 80-90°C @ 0.075mm.
- Combine [(2-thiophene)sulfonyl]isocyanate (680mg, 3.1mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (0.85g, 3.6mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound as a yellow solid (1.03g, 80%); mp 215-16°C.
- Anal. Calcd for C₁₅H₁₀Cl₂N₂O₄S: C, 43.17; H, 2.42; N. 6.71;
Found: C, 43.21; H, 2.19; N, 6.73. -
- Anal. Calcd for C₁₄H₈Cl₂N₂O₄S·E₂O: C, 39.92; H, 2.39; N, 6.65;
Found: C, 39.95; H, 2.21; N, 6.70. -
- Combine 4-(methoxy)benzenesulfonyl chloride (8.24g, 0.04mol) and concentrated ammonium hydroxide (80mL). Seal and stir for 16 hours at room temperature. Heat at 90°C to remove the ammonia and then add hydrochloric acid (1mL of a 12N solution). Cool, filter and dry to give the title compound as an off-white solid (5.63g, 76%); mp 109-10°C.
- Combine 4-(methoxy)benzenesulfonamide (1.20g, 6.4mmol) and oxalyl chloride (15mL) and reflux for 9 hours. Evaporate the excess oxalyl chloride in vacuo to give the title compound.
- Combine N-[(1-oxo-2-oxo-2-chloro)ethyl]-4-(methoxy)benzenesulfonamide (1.78g, 6.4mmol) and o-dichlorobenzene (25mL). Reflux for 16 hours then remove the solvent by distillation (6mm Hg vacuum through a column packed with glass helices). Purify by distillation to give the title compound (1.67g, 79%); bp 111-12°C @ 0.075mm.
- Combine [4-(methoxy)benzenesulfonyl]isocyanate (1.06g, 7.8mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.03g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound as a yellow solid (1.56g, 91%); mp 224-5°C.
-
- Combine 5,7-dichloro-4-[4-(methoxy)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.45g, 3.3mmol), lithium hydroxide hydrate (350mg, 8.2mmol), water (6mL) and methanol (30mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter the light yellow solid, wash with water and dry to give the title compound (1.20g, 85%); mp 206-8°C (dec).
- Anal. Calcd for C₁₇H₁₂Cl₂N₂O₅S: C, 47.79; H, 2.84; N, 6.76;
Found: C, 47.65; H, 2.84; N, 6.45. -
- Combine benzenesulfonyl isocyanate (824mg, 4.5mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.03g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound as a yellow solid (1.67g, 93%); mp 218-19°C.
-
- Combine 5,7-dichloro-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (5.lg, 12mmol), lithium hydroxide hydrate (1.35g, 32.2mmol), water (30mL) and methanol (900mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter the light yellow solid, wash with water and dry to give the title compound (4.12g, 84%); mp 204-5°C (dec).
- Anal. Calcd for C₁₀H₁₀Cl₂N₂O₄S·3/8H₂O: C, 47.58; H, 2.68; N, 6.94;
Found: C, 47.21; H, 2.56; N, 6.92. -
- Combine p-toluenesulfonyl isocyanate (599mg, 4.5mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.03g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound as a yellow solid (1.79g, 96%); mp 217-19°C.
- Anal. Calcd for C₁₈H₁₄Cl₂N₂O₄S: C, 50.84; H, 3.32; N, 6.59;
Found: C, 50.81; H, 3.02; N, 6.38. -
- Combine 5,7-dichloro-4-[(4-methyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.20g, 2.9mmol), lithium hydroxide hydrate (245mg, 5.8mmol), water (6mL) and methanol (30mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter the light yellow solid, wash with water and dry to give the title compound (1.07g, 92%); mp 308-11°C (dec).
- MS (M+ = 411 with di-chloro pattern)
-
- Combine 4-chlorobenzenesulfonyl isocyanate (693mg, 4.5mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.03g, 3.8mmol) and propionitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound as a yellow solid (1.72g, 88%); mp 260-62°C (dec).
- Anal. Calcd for C₁₇H₁₁Cl₃N₂O₄S: C, 45.81; H, 2.49; N, 6.29;
Found: C, 45.76; H, 2.29; N, 6.28. -
- Combine 5,7-dichloro-4-[(4-chloro)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.26g, 2.9mmol), lithium hydroxide hydrate (245mg, 5.8mmol), water (6mL) and methanol (30mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter the light yellow solid, wash with water and dry to give the title compound (1.22g, 100%); mp 295-8°C.
- MS (M+ = 431 with tri-chloro pattern)
-
- Combine trifluoromethylsulfonyl isocyanate (788mg, 4.5mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.03g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound;mp 265-6°C (dec).
Anal. Calcd for C₁₂H₇Cl₂F₃N₂O₄S: C, 35.75; H, 1.75; N. 6.95;
Found: C, 35.72; H, 1.57; N, 6.87. -
- Combine 5,7-dichloro-4-[trifluoromethylsulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.14g, 2.9mmol), lithium hydroxide hydrate (245mg, 5.8mmol), water (6mL) and methanol (30mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter, wash with water and dry to give the title compound.
-
- Mix 4-ethyl-2-nitroaniline (16.6g, 0.1mol) in water (400mL) and add 48% hydrobromic acid (1kg). Add bromine (16g, 0.1mol) with stirring and stir for 1 hour. Dilute to 2L and cool to 7°C. Filter, wash with water and dry to give 4-ethyl-2-nitro-6-bromoaniline.
- Dissolve 4-ethyl-2-nitro-6-bromoaniline (6.62g, 27mmol) in ethanol (40mL). Add, by dropwise addition, concentrated sulfuric acid (5mL) and heat at reflux, adding sodium nitrite (4.55g, mmol) in small portions over 25 minutes. Stir at room temperature for several hours, pour onto ice and extract into ethyl acetate. Wash with water (3X) and brine (3X). Dry (MgSO₄) and evaporate the solvent in vacuo and purify by silica gel chromatography to give 3-bromo-5-ethylnitrobenzene.
- Dissolve 3-bromo-5-ethylnitrobenzene (6.21g, 27mmol) in acetic acid (40mL) and ethanol (30mL) and treat with iron powder (2.7g). Reflux for 3 hours, filter through Celite and evaporate the solvent in vacuo. Purify by silica gel chromatography to give 3-bromo-5-ethylaniline.
- Dissolve 3-bromo-5-ethylaniline (4.7g, 23.5mmol) in methanol (100mL) and add diethylacetylene dicarboxylate (5.5mL) at room temperature. Reflux for 10 hours and cool to room temperature. Evaporate the solvent in vacuo and add to diphenylether (100mL) at 250°C. Stir for 15 minutes and let cool to room temperature. Add hexane (500mL) and filter the precipitate. Purify by silica gel chromatography to give 5-ethyl-7-bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester
- Combine benzenesulfonyl isocyanate (824mg, 4.5mmol), 5-ethyl-7-bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester (1.23g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound.
-
- Combine 5-ethyl-7-bromo-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester (1.34g, 2.9mmol), lithium hydroxide hydrate (245mg, 5.8mmol), water (6mL) and methanol (30mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter to give the title compound.
-
- Mix water (1800mL), 48% hydrobromic acid (3000mL) and 4-fluoro-2-nitroaniline (75g, 0.48mol) . Cool to 25°C and add, by dropwise addition over 30 minutes, bromine (78.6g, 0.48mol). Stir at room temperature for 45 minutes and dilute with ice-water (4200mL) to cool to 5°C. Filter, wash with water and dry (P₂O₅) to give 4-fluoro-2-nitro-6-bromoaniline (107.2g, 95%); mp 71.5-72.5°C.
- Anal. Calcd for C₆H₄BrFN₂O₂: C, 30.66; H, 1.72; N, 11.92;
Found: C, 30.68; H, 1.74; N, 11.53. - Mix water (60mL), concentrated sulfuric acid (60mL) and 4-fluoro-2-nitro-6-bromoaniline (9.65g, 41mmol). Cool to 0°C and add solid sodium nitrite (4.25g, 61mmol) in small portions at such a rate as not to exceed 5°C. Stir for 30 minutes and add ferrous sulfate heptahydrate (5.6g, 20.5mmol) and ethanol (18mL). Stir with warming to room temperature over 2 hours. Add water (200mL), separate the organic phase and wash the aqueous phase with methylene chloride (2X). Combine the organic phases, dry (MgSO₄) and evaporate the solvent in vacuo. Purify by silica gel chromatography (5% ethyl acetate/hexane) to give 3-bromo-5-fluoronitrobenzene (4.5g); bp 65-70°C @ 1.0mm Hg.
- Anal. Calcd for C₅H₃BrFNO₂: C, 32.75; H, 1.37; N, 6.37;
Found: C, 32.67; H, 1.27; N, 6.16. - Mix methanol (17mL) and 12N hydrochloric acid (18mL) and add iron powder (5.34g, 95mmol) until the mixture refluxes. Stir and allow to come to room temperature. Add water (200mL) and separate the organic phase. Wash the aqueous phase with methylene chloride (2X), combine the organic phases and dry (MgS0₄). Evaporate the solvent in vacuo and purify by silica gel chromatography (10% ethyl acetate/hexane) and distill to give 3-fluoro-5-bromoaniline; bp 85-90°C @ 0.5mm Hg.
- Anal. Calcd for C₆H₅BrFN: C, 37.92; H, 2.65; N, 7.37;
Found: C, 37.87; H, 2.54; N, 7.35. - Combine 3-fluoro-5-bromoaniline (5.0g, 26.3mmol), dimethylacetylene dicarboxylate (3.25mL) and methanol (150mL). Heat at reflux for 3 hours, cool to room temperature and stir for 3 days. Evaporate the solvent in vacuo, purify by silica gel chromatography (10% ethyl acetate/hexane) to give 3-fluoro-5-bromo-N-(dimethylfumaryl)aniline (0.48g).
- Anal. Calcd for C₁₂H₁₁BrFNO₄: C, 43.39; H, 3.34; N, 4.22;
Found: C, 42.97; H, 3.02; N, 3.98. - Mix 3-fluoro-5-bromo-N-(dimethylfumaryl)aniline (7.8g, 23mmol) and diphenyl ether (117g). Heat at reflux for 20 minutes. Add hexane (800mL) and filter. Purify by silica gel chromatography (40% ethyl acetate/hexane) and crystallize (acetonitrile) to give 5-bromo-7-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, methyl ester; mp 289-289.5°C (dec).
- Anal. Calcd for C₁₁H₇BrFNO₃: C, 44.02; H, 2.35, N, 4.67;
Found: C, 44.18; H, 2.26; N, 4.55. - Combine benzenesulfonyl isocyanate (824mg, 4.5mmol), 5-bromo-7-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.14g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give the title compound.
-
- Combine 5-bromo-7-fluoro-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.23g, 2.9mmol), lithium hydroxide hydrate (245mg, 5.8mmol), water (6mL) and methanol (30mL). Stir under a nitrogen atmosphere for 6 hours. Dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter to give the title compound.
-
- Combine [2-chlorobenzenesulfonyl]isocyanate (10g, 46mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (5g, 18mmol) and acetonitrile (36mL). Reflux for 4 hours, cool and filter. Recrystallize (acetonitrile) to give the title compound (7.1g, 87%); mp 219.5-220.5°C.
- Anal. Calcd for C₁₇H₁₁Cl₃N₂O₄S: C, 45.81; H, 2.49; N, 6.29;
Found: C, 45.79; H, 2.67; N, 6.44. -
- Combine water (9mL), methanol (45mL), lithium hydroxide hydrate (0.47g, 11.2mmol) and 5,7-dichloro-4-[2-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (2g, 4.5mmol). Seal and stir overnight. Evaporate the methanol in vacuo and dilute with water (100mL). Adjust to pH2 with 12N hydrochloric acid, filter and wash with water. Crystallize (acetone/water) to give the title compound (1.62g, 83%); mp 226.5-228°C (dec).
- Anal. Calcd for C₁₆H₉Cl₃N₂O₄S: C, 44.51; H, 2.10; N, 6.49;
Found: C, 44.28; H, 2.29; N, 6.09. -
- Combine oxalyl chloride (25mL) and 3-chlorobenzenesulfonamide (4.3g, 23mmol) and reflux overnight. Remove oxalyl chloride in vacuo and combine the resulting residue with o-dichlorobenzene (25mL) and reflux. Evaporate the solvent in vacuo and distill to give [3-chlorobenzenesulfonyl]isocyanate (2g, 40%); bp 92-5°C.
- Combine [3-chlorobenzenesulfonyl]isocyanate (2g, 9.2mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.67g, 6.1mmol) and acetonitrile (2mL). Reflux overnight, add methanol and stir for 1 hour at room temperature. Adsorb onto silica gel and purify by silica gel chromatography (10% ethyl acetate/hexane) and recrystallize (acetonitrile) to give the title compound (0.74g, 27%); mp 248-58°C.
- Anal. Calcd for C₁₇H₁₁Cl₃N₂O₄S: C, 45.81; H, 2.49; N, 6.29;
Found: C, 45.91; H, 2.61; N, 6.11. -
- Combine water (4mL), methanol (12mL), lithium hydroxide hydrate (0.17g, 4mmol) and 5,7-dichloro-4-[3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (0.6g, 1.3mmol). Stir for 4 hours at room temperature, dilute with water (100mL) and adjust to pH 2 with 12N hydrochloric acid. Filter and recrystallize (acetone/water) to give the title compound (0.47g, 84%); mp 210-11°C (dec).
- Anal. Calcd for C₁₆H₉Cl₃N₂O₄S: C, 44.51; H, 2.10; N, 6.49;
Found: C, 44.42; H, 2.22; N, 6.21. - The following compounds can be prepared analogously to those described in Examples 1-24:
- 5,7-dichloro-4-[4-(hydroxy)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dibromo-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-Bromo-7-chloro-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- The compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃ and B is a group represented NH(CO)OR₃ and D is represented by C(O)OR₁, wherein R1 is C₁-C₆ alkyl or C(O)NR₁R₂ wherein R₁ and R₂ are as previously defined, the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented NHC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃, or NHSO₂C₆H₅ and D is represented by C(O)OR₁, wherein R₁ is hydrogen and the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF3, B is a group represented NH₂ and D is represented by C(O)OR₁, wherein R1 is hydrogen may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme B. In Scheme B, all substituents unless otherwise indicated are as previously defined.
D' = C(O)OR₁' or C(O)NR₁R₂
R₁' = C₁-C₆ alkyl - Scheme B provides a general synthetic scheme for preparing the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF3, B is a group represented NH(CO)OR₃ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl or C(O)NR₁R₂ wherein R₁ and R₂ are as previously defined, the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF3, B is a group represented NHC(O)R₃, NH(CO)OR₃, NHC(O)NHR₃, NHSO₂CF₃, or NHSO₂C₆H₅ and D is represented by C(O)OR₁, wherein R₁ is hydrogen and the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented NH₂ and D is represented by C(O)OR₁, wherein R₁ is hydrogen.
- In step a, the appropriate aminobenzenesulfonyl chloride of structure (9) is amidated with ammonium hydroxide (2) to give the corresponding aminobenzene sulfonamide of structure (10) as described previously in Scheme A, step a.
- In step b, both sulfonamide and amino functionalities of the appropriate aminobenzene sulfonamide of structure (10) are converted to the corresponding (isocyanato)benzenesulfonyl isocyanate of structure (11).
- For example, the appropriate aminobenzenesulfonamide of structure (10) is contacted with a molar excess of either phosgene, triphosgene or oxalyl chloride, phosgene being preferred. The reactants are typically contacted in a suitable organic solvent such as nitrobenzene. The reactants are typically stirred together at a temperature range of from -10°C to reflux and for a period of time ranging from 5-24 hours. The (isocyanato)benzenesulfonyl isocyanate of structure (11) is recovered from the reaction zone by evaporation of the volatiles.
- In step c, the appropriate (isocyanato)benzenesulfonyl isocyanate of structure (11) is first reacted with an appropriate 4-oxo-1,4-dihydroquinoline of structure (6) to give the intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline. The isocyanato functionality of the intermediate 4-(isocyanato)benzene)sulfonimide-1,4-dihydroquinoline is then decomposed by the addition of an appropriate alcohol of the formula R₃OH to give the corresponding 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline of structure (12).
- For example, the appropriate (isocyanato)benzenesulfonyl isocyanate of structure (11) is contacted with a slight molar deficiency of an appropriate 4-oxo-1,4-dihydroquinoline of structure (6). The reactants are typically contacted in a polar anhydrous organic solvent such as acetonitrile or propionitrile. The reactants are typically stirred together for a period of time ranging from 4-24 hours and at a temperature range of from room temperature to reflux. The intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline is recovered from the reaction zone by filtration. The intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline is then treated with a molar excess of the appropriate alcohol of the formula R₃OH. The reactants are typically stirred together at reflux temperature for a period of time ranging from 2-24 hours. The 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline of structure (12) is recovered from the reaction zone by filtration. It may be purified by recrystallization as is known in the art.
- Alternatively, the isocyanato functionality of the appropriate intermediate 4-[(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline may be decomposed by the addition of an appropriate amine of the formula H₂NR₃ to give the corresponding 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- In optional step d, both the carbamoyl functionality and the ester or amide functionality of the appropriate 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline of structure (12) are hydrolyzed with a base such as sodium hydroxide to give the corresponding 4-[(amino)benzenesulfonimide)-1,4-dihydroquinoline-2-carboxylic acid of structure (13) as described previously in Scheme A, optional step e.
- The 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (13) wherein A is a group represented by C(O)OR₁ wherein R₁ is C₁-C₄ alkyl, or C(O)NR₁R₂ can be prepared as described later in Scheme D, step a and optional step b₁ or optional step b₂.
- In optional step e, the amino functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) can be functionalized to give either the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14), 4-[(ureido)benzenesulfonimide]-l,4-dihydroquinoline of structure (14), 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) or 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- For example, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) can be acylated to give the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- For example, the appropriate 4-[(amino)benzenesulfonimide-]-1,4-dihydroquinoline of structure (13) is contacted with a molar equivalent of the appropriate acylating agent represented by the formula R₃COCl. The reactants are typically contacted in a suitable non-nucleophilic organic base such as pyridine or an aqueous solvent such as dioxane/water buffered to pH 10 with a base such as sodium hydroxide. The reactants are typically stirred together at room temperature for a period of time ranging from 2-24 hours. The 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) is recovered from the reaction zone by extractive methods as is known in the art.
- Similarly, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) can be converted to the corresponding 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- For example, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) is contacted with a molar equivalent of the appropriate isocyante of the formula R₃NCO. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran. The reactants are typically stirred together at room temperature for a period of time ranging from 1-5 hours. The 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) is recovered from the reaction zone by extractive methods as is known in the art.
- In addition, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) can be converted to the corresponding 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) or 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14).
- For example, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) is contacted with a molar excess of trifluoromethanesulfonic anhydride, and a molar excess of a base such as diisopropylethylamine. The reactants are typically contacted in methylene chloride. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from -78°C to 85°C. The 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) is recovered from the reaction zone by extractive methods as is known in the art. Similarly, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline of structure (13) is converted to the corresponding 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline of structure (14) using benzenesulfonyl chloride instead of trifluoromethanesulfonic anhydride.
- Starting materials for use in Scheme B are readily available to one of ordinary skill in the art. For example, p-isocyanatobenzenesulfonyl isocyanate is described in J.Org. Chem., 30 1260-2 1965 and certain substituted aminobenzene sulfonamides of structure (10) are described in Arzneim.-Forsch./Drug Res. 28(8) 1331-4 1978, J. Med. Chem. 21(9) 845 1978, Gazz. Chim. Ital. 78 275 1948 and J.Pharm.Parmacol. 12 705 1960.
- The following examples present typical syntheses as described in Scheme B. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way.
-
- Combine 4-isocyanatobenzenesulfonyl isocyanate (45.8g, 0.2mol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (27.2g, 0.1mol) and acetonitrile (400mL). Reflux for 4 hours, cool and add methanol (120mL) and reflux for several hours. Cool, filter and wash with acetonitrile. Triturate with boiling methanol (3L) by stirring at reflux for 1 hour. Cool while continuing to stir and collect the solid by filtration to give title compound (40.6g, 84%); mp 251.1-252.5°C.
- Anal. Calcd for C₁₉H₁₅Cl₂N₃O₆S: C, 47.12; H, 3.12; N, 8.67;
Found: C, 46.96; H, 3.09; N, 8.76. -
- Combine 4-isocyanatobenzenesulfonyl isocyanate (4.9g, 0.021mol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (3.3g, 0.012mol) and acetonitrile (50mL). Reflux for 2.5 hours, cool and add ethanol (25mL) and reflux for several hours. Cool and evaporate the solvent in vacuo. Triturate with boiling methanol (1.6L) by stirring at reflux for 1 hour. Cool while continuing to stir and collect the solid by filtration to give the title compound (5.5g, 92%); mp 256-257°C.
- Anal. Calcd for C₂₀H₁₇Cl₂N₃O₆S: C, 48.20; H, 3.44; N, 8.43;
Found: C, 48.21; H, 3.39; N, 8.36. -
- Combine 4-isocyanatobenzenesulfonyl isocyanate (4.9g, 0.021mol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (3.3g, 0.012mol) and acetonitrile (50mL). Reflux for 2.5 hours, cool and add butanol (25mL) and reflux for several hours. Cool and evaporate the solvent in vacuo. Recrystalize (methanol, 1L), collect the solid by filtration to give the title compound (4.14g, 66%); mp 219-220°C.
- Anal. Calcd for C₂₂H₂₁Cl₂N₃O₆S: C, 50.19; H, 4.02; N, 7.98;
Found: C, 50.16; H, 4.01; N, 7.85. -
- Combine 4-isocyanatobenzenesulfonyl isocyanate (4.9g, 0.021mol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (3.3g,0.012mol) and acetonitrile (50mL). Reflux for 2.5 hours, cool to 0°C and add 40% aqueous methylamine (10mL) and stir at room temperature for several hours. Evaporate the solvent in vacuo and triturate with methanol. Collect the solid by filtration and dissolve in 1600 ml of methanol/water 1/1, add 30 ml 1 N HCl, 400 ml of water and cool to 0°C. Collect the solid by filtration to give title compound (2.40g, 41%); mp 250-2°C (dec).
- Anal. Calcd for C₁₉H₁₆Cl₂N₄O₅S: C, 47.21; H, 3.34; N, 11.59;
Found: C, 47.17; H, 3.35; N, 11.62. -
- Combine 5,7-dichloro-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (378mg, 0.78mmol), sodium hydroxide (0.94g, 2.3mmol), water (1.4mL), and methanol (6mL). Stir at reflux temperature under a nitrogen atmosphere for 36 hours. Remove solvent in vacuo and dilute with water (100mL). Adjust to pH 2 with 12N hydrochloric acid. Filter to give the title compound; mp 178-180.5°C (dec) (acetone/water).
- Anal. Calcd for C₁₆H₁₁Cl₂N₃O₄S.0·75H₂O: C, 45.12; H, 2.96; N, 9.87;
Found: C, 45.11; H, 2.97; N. 9.97. -
- Dissolve 4-amino-3-chlorobenzenesulfonamide (0.96g, 5mmol) in chlorobenzene (10% solution) and distill the mixture to remove any traces of water. Cool to 100°C and add n-butyl isocyanate (99mg, 1mmol). Heat to reflux and add, by dropwise addition, oxalyl chloride (1.5mL). Purge with nitrogen at 130-132°C for 30 minutes and distill to give 3-chloro-4-isocyanatobenzenesulfonyl isocyanate.
- Combine 3-chloro-4-isocyanatobenzenesulfonyl isocyanate (52mg, 0.2mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (27.2mg, 0.1mmol) and acetonitrile (40mL). Reflux for 4 hours and add methanol (12mL) and reflux for several hours. Cool, filter and wash with acetonitrile. Triturate with boiling methanol (3mL) by stirring at reflux for 1 hour. Cool while continuing to stir and collect the solid by filtration to give title compound.
-
- Dissolve 4-amino-2-chlorobenzenesulfonamide (0.96g, 5mmol) in chlorobenzene (10% solution) and distill'the mixture to remove any traces of water. Cool to 100°C and add n-butyl isocyanate (99mg, lmmol). Heat to reflux and add, by dropwise addition, oxalyl chloride (1.5mL). Purge with nitrogen at 130-132°C for 30 minutes and distill to give 2-chloro-4-isocyanatobenzenesulfonyl isocyanate.
- Combine 4-isocyanato-2-chlorobenzenesulfonyl isocyanate (52mg, 0.2mmol), 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (27.2mg, 0.lmmol) and acetonitrile (40mL). Reflux for 4 hours and add methanol (12mL) and reflux for several hours. Cool, filter and wash with acetonitrile. Triturate with boiling methanol (3mL) by stirring at reflux for 1 hour. Cool while continuing to stir and collect the solid by filtration to give title compound.
-
- Combine 5,7-dichloro-4-[4-(methylcarbamoyl)-3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (406mg, 0.78mmol), sodium hydroxide (0.94g, 2.3mmol), water (1.4mL), and methanol (6mL). Stir at reflux temperature under a nitrogen atmosphere for 36 hours. Remove solvent in vacuo and dilute with water (100mL). Adjust to pH 2 with 12N hydrochloric acid. Filter to give the title compound.
-
- Combine 5,7-dichloro-4-[4-(methylcarbamoyl)-2-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (406mg, 0.78mmol), sodium hydroxide (0.94g, 2.3mmol), water (1.4mL), and methanol (6mL). Stir at reflux temperature under a nitrogen atmosphere for 36 hours. Remove solvent in vacuo and dilute with water (100mL).
- Adjust to pH 2 with 12N hydrochloric acid. Filter to give the title compound.
-
- Mix 5,7-dichloro-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid (4.13g, 10mmol) and pyridine (25mL). Cool to 10°C and add, by dropwise addition, acetyl chloride (869mg, 11mmol). Allow to warm to room temperature and stir for 16 hours. Evaporate in vacuo, treat with water and filter to give the title compound.
-
- Mix 5,7-dichloro-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid (0.82g, 2mmol) and pyridine (5mL). Cool to 10°C and add, by dropwise addition, benzoyl chloride (0.58mL, 5mmol). Allow to warm to room temperature and stir for 16 hours. Evaporate in vacuo, treat with water and filter to give the title compound.
-
- Combine 4-isocyanatobenzenesulfonyl isocyanate (1.01g, 4.5mmol), 5-bromo-7-fluoro-4-hydroxyquinoline-2-carboxylic acid, methyl ester (1.14g, 3.8mmol) and acetonitrile (8mL). Reflux for 16 hours, cool and filter to give 5-bromo-7-fluoro-4-[4-(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester.
- Treat 5-bromo-7-fluoro-4-[4-(isocyanato)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (2.24g, 4.5mmol) with methanol (125mL). Heat at reflux for 5 hours and evaporate the solvent in vacuo. Purify by chromatography to give the title compound.
-
- Combine 5-bromo-7-fluoro-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (401mg, 0.78mmol), sodium hydoxide (0.94g, 2.3mmol), water (1.4mL), and methanol (6mL). Stir at reflux temperature under a nitrogen atmosphere for 36 hours. Remove solvent in vacuo and dilute with water (100mL). Adjust to pH 2 with 12N hydrochloric acid. Filter to give the title compound.
- The following compounds can be prepared analogously to those described in Examples 25-37:
- 5,7-dibromo-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5-bromo-7-chloro-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-dibromo-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-bromo-7-chloro-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-dibromo-4-[4-(acetylamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-bromo-7-chloro-4-[4-(acetylamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-bromo-7-chloro-4-[4-(trifluoromethylsulfonamido)-benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-bromo-7-chloro-4-[4-(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-bromo-7-fluoro-4-[4-(acetylamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid.
- 5,7-dichloro-4-[4-(trifluoromethylsulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid.
- The compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF3,, B is a group represented NH(CO)OR₃ and D is represented by C(O)OR1, wherein R₁ is hydrogen may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme C. In Scheme C, all substituents unless otherwise indicated are as previously defined.
- Scheme C provides a general synthetic procedure for preparing the compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented by NH(CO)OR₃ and D is represented by C(O)OR₁, wherein R₁ is hydrogen.
- The methyl ester functionality of the appropriate 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (15) is hydrolyzed to give the corresponding 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (16).
- For example, the appropriate 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (15) is contacted with a molar excess of an appropriate base such as lithium hydroxide. The reactants are typically contacted in a suitable solvent mixture such as methanol/water. The reactants are typically stirred together at room temperature for a period of time ranging from 2-10 hours. The 4-[(alkylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (16) is recovered from the reaction zone by extractive methods as is known in the art.
- Starting materials for use in Scheme C are readily available to one of ordinary skill in the art.
- The following examples present a typical synthesis as described in Scheme C. The examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way.
-
- Combine 5,7-dichloro-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (242mg, 0.5mmol), lithium hydroxide hydrate (46mg, 1.5mmol), water (1mL) and methanol (3mL). Stir overnight at room temperature. Remove the methanol in vacuo and dilute with water (50mL). Adjust to pH 2 with 12N hydrochloric acid and filter. Crystallize from acetone/water to give the title compound (0.14g, 60%); mp 201-202°C (dec).
- Anal. Calcd for C₁₈H₁₃Cl₂N₃O₆S·H₂O: C, 44.27; H, 3.10; N, 8.61;
Found: C, 44.43; H, 3.16; N, 8.55. -
- Combine 5,7-dichloro-4-[4-(ethylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (2.0g, 4.0mmol), lithium hydroxide hydrate (0.34g, 8mmol), water (25mL) and methanol (50mL). Stir overnight at room temperature. Remove the methanol in vacuo and dilute with water (100mL). Adjust to pH 2 with 12N hydrochloric acid and filter. Crystallize twice from acetone/water to give the title compound (1.35g, 70%); mp 162-62°C (dec).
- Anal. Calcd for C₁₉H₁₅Cl₂N₃O₆S·H₂O: C, 45.42; H, 3.41; N, 8.37;
Found: C, 45.38; H, 3.43; N, 8.45. -
- Combine 5,7-dichloro-4-[4-(butylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (2.0g, 3.8mmol), lithium hydroxide hydrate (0.319g, 7.5mmol), water (25mL) and methanol (50mL). Stir overnight at room temperature. Remove the methanol in vacuo and dilute with water (100mL). Adjust to pH 2 with 12N hydrochloric acid and filter. Crystallize from acetone/water to give the title compound (1.84g, 99%); mp 204-205°C (dec).
- Anal. Calcd for C₂₁H₁₉Cl₂N₃O₆S·H₂O: C, 47.56; H, 3.99; N, 7.92;
Found: C, 47.48; H, 3.97; N, 4.12. - The following compounds can be prepared analogously to those described in Examples 38-40:
- 5,7-Dibromo-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-Bromo-7-fluoro-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5-Bromo-7-chloro-4-[4-(methylcarbamoyl)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid.
- The compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented NH₂, NHC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃, or NHSO₂C₆H₅ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl or C(O)NR₁R₂ may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme D. In Scheme D, all substituents unless otherwise indicated are as previously defined.
R₁' = C₁-C₆ alkyl - Scheme D provides a general synthetic scheme for preparing compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented NH₂, NBC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃, or NHSO₂C₆H₅ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl, or C(O)NR₁R₂.
- In step a, the carboxylic acid functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (13) is esterified to give the corresponding 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17).
- For example, the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (13) is contacted with a molar excess of methanolic hydrochloric acid. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to 60°C. The 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is recovered from the reaction zone by extractive methods as is known in the art.
- In optional step b₁, the methyl ester functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is amidated to give the corresponding 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, carboxyamide of structure (18).
- For example the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is contacted with a molar equivalent of an appropriate amine of the formula NHR₁R₂ and a catalytic amount of a amidation catalyst such as 2-hydroxypyridine or potassium cyanide. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux. The 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (18) is recovered from the reaction zone by extractive methods as is known in the art.
- In optional step b₂, the methyl ester functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is transesterified to give the corresponding 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (19).
- For example the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (17) is contacted with a molar excess of an appropriate alcohol of the formula R₁OH and a catalytic amount of an acid such as concentrated sulfuric acid. The reactants are typically stirred together for a period of time ranging from 2-24 hours and at a temperature range of from room temperature to reflux. The 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (19) is recovered from the reaction zone by extractive methods as is known in the art.
- In optional step c₁, the amine functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (18) can be functionalized to give either the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20), 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20), 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20) or 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxyamide of structure (20) as described previously in Scheme B, optional step e.
- In optional step c₂, the amine functionality of the appropriate 4-[(amino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (19) can be functionalized to give the corresponding 4-[(amido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21), 4-[(ureido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21), 4-[(trifluoromethanesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21) or 4-[(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (21) as described previously in Scheme B, optional step e.
- Starting materials for use in Scheme D are readily available to one of ordinary skill in the art.
- The following examples present typical syntheses as described in Scheme D. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way.
-
- Dissolve 5,7-dichloro-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid (413mg, 1mmol) in 0.5N methanolic hydrochloric acid (50mL). Stir at room temperature for 16 hours, cool and evaporate the solvent in vacuo. Add water to give a solid and filter to give the title compound; mp 219-223°C.
- Anal. Calcd for C₁₇H₁₃Cl₂N₃O₄S: C, 47.90; H, 3.07; N, 9.86;
Found: C, 47.94; H, 2.97; N, 9.59. -
- Combine 5,7-dichloro-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (4.27g, 10mmol) in pyridine (25mL). Cool to 10°C and add, by dropwise addition, acetyl chloride (869mg, 11mmol). Allow to warm to room temperature and evaporate the pyridine in vacuo. Triturate with water and filter to give the title compound.
- The following compounds can be prepared analogously to those described by Scheme D:
- 5,7-Dibromo-4-[4-(acetylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-dibromo-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-dimethylcarboxamide;
- 5-bromo-7-chloro-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5-bromo-7-fluoro-4-[4-aminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5,7-dibromo-4-[4-(acetylamido)benzenesulfonimide]-1,4-dihydroquinoline-2-dimethylcarboxamide;
- 5-bromo-7-chloro-4-[4-(acetylamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5-bromo-7-chloro-4-[4-(trifluoromethylsulfonamido)benzenesulfonimide]-l,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5-bromo-7-chloro-4-[4-(benzenesulfonamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester;
- 5-bromo-7-fluoro-4-[4-(acetylamido)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester.
- 5,7-dichloro-4-[4-(trifluoromethylsulfonamido)-phenylsulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester.
- The compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented by NR₁R₂ and D is represented by C(O)OR₁ wherein R₁ is hydrogen may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme E. In Scheme E all substituents, unless otherwise indicated are as previously defined.
- Scheme E provides a general synthetic scheme for preparing compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented by NR₁R₂ and D is represented by C(O)OR₁ wherein R₁ is hydrogen.
- The aromatic fluoride of the appropriate 4-[fluorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (22) is displaced with an appropriate amine of structure (23) to give the 4-[dialkylaminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (24).
- For example, the appropriate 4-[fluorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (22) is contacted with an excess amount of an appropriate amine of structure (23). The reactants are typically contacted in a suitable polar organic solvent, such as dimethyl sulfoxide. The reactants are typically stirred together for a period of time ranging from 4-10 hours and at a temperature range of from 50-95°C. The 4-[dialkylaminobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (24) is recovered from the reaction zone by extractive methods as is known in the art. It may be purified by silica gel chromatography.
- Starting materials for use in Scheme E are readily available to one of ordinary skill in the art.
- The following example presents a typical synthesis as described in Scheme E. These example is understood to be illustrative only and is not intended to limit the scope of the present invention in any way.
-
- Pass dimethylamine gas through a solution of 5,7-dichloro-4-[4-fluorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid (12.5g, 0.03mol) in dimethyl sulfoxide (100mL) and keep at 80°C for several hours and until absorption of the gas ceased. Pour the solution into water (600mL), acidify to pH 4 with hydrochloric acid and filter to give the title compound.
- The following compounds can be prepared by analogy to that described in Example 43:
- 5,7-Dichloro-4-[4-(diethylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid;
- 5,7-Dichloro-4-[4-(t-butylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid.
- The compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented by NR₁R₂ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl, or C(O)NR₁R₂ may be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme F. In Scheme F all substituents, unless otherwise indicated are as previously defined.
- Scheme F provides a general synthetic scheme for preparing compounds of Formula I wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented by NR₁R₂ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl, or C(O)NR₁R₂.
- In step a, the carboxylic acid functionality of the appropriate 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid of structure (24) is esterified to give the corresponding 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (25) as described previously in Scheme D, step a.
- In optional step b₁, the methyl ester functionality of the appropriate 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (25) is amidated to give the corresponding 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxamide of structure (26) as described previously in Scheme E, optional step b₁.
- In optional step b₂, the methyl ester functionality of the appropriate 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester of structure (25) is transesterified to give the corresponding 4-[(dialkylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic ester of structure (27) as described previously in Scheme D, optional step b₂.
- Starting materials for use in Scheme F are readily available to one of ordinary skill in the art.
- The following example presents a typical synthesis as described in Scheme F. This example is understood to be illustrative only and is not intended to limit the scope of the present invention in any way.
-
- Dissolve 5,7-dichloro-4-[4-(dimethylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid (4.41g, 1mmol) in 1N methanolic hydrochloric acid (50mL). Heat at 60°C for 16 hours, cool and evaporate the solvent in vacuo to give the title compound.
- The following compounds can be prepared analogously to that described by Scheme F:
- 5,7-Dichloro-4-[4-(dimethylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester;
- 5,7-Dichloro-4-[4-(dimethylamino)benzenesulfonimide]-1,4-dihydroquinoline-2-dimethylcarboxamide.
Claims (22)
- A compound of the formula:
-(CY₂)nCY₃ , -(CT₂)nCT₃
- A compound according to claim 1 in which D is represented by C(O)OR₁.
- A compound according to claim 1 in which D is represented by C(O)N₁R₂.
- A compound according to claim 1 in which X is represented by -(CY₂)nCY₃.
- A compound according to claim 1 in which X is represented by -(CT₂)nCT₃.
- A compound according to claim 1 in which X is a phenyl derivative.
- A compound according to claim 1 in which X is a 2-thiophene derivative.
- A compound according to claim 1 in which X is a 3-thiophene derivative.
- A compound according to claim 1 in which Z is a 5,7-halogen substituent.
- A method for the preparation of a pharmaceutical composition comprising combining a compound as defined in claim 1, including those compounds wherein 1) D is C(O)OCH₃ X is phenyl in which A is para-methyl and B is hydrogen and Z is hydrogen, or a 5,7-dichioro substituent; 2) D is C(O)OC₂H₅ X is phenyl in which A is para-methyl and B is hydrogen, and then Z is 6-methoxy, 7-methoxy or 5,8-dimethoxy with a pharmaceutically acceptable carrier.
- A method according to claim 10 wherein the pharmaceutical composition prepared is useful in antagonizing the effects of excitatory amino acids upon the NMDA receptor complex.
- A method according to claim 10 wherein the pharmaceutical composition prepared is useful in the treatment of epilepsy.
- A method according to claim 10 wherein the pharmaceutical composition prepared is useful in the treatment of neurodegenerative diseases.
- A method according to claim 10 wherein the pharmaceutical composition prepared is useful in preventing ischemic/hypoxic/hypoglycemic damage to cerebral tissue.
- A method according to claim 10 wherein the pharmaceutical composition prepared is useful in the treatment of anxiety.
- A method according to claim 10 wherein the pharmaceutical composition prepared is useful in producing an analgesic effect.
- A method according to claim 10 wherein the pharmaceutical composition prepared is useful in the treatment of migraine.
- A method according to claim 10 comprising the additional use of probenecid to form either a two different or a single dosage form.
- A process for preparing a compound according to claim 1 comprising:a) for those compounds wherein X is a group represented by -(CY₂)nCY₃, -(CT₂)nCT₃, a phenyl derivative, a 2-thiophene derivative or a 3-thiophene derivative, A is a group represented hydrogen, halogen, OH, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃ or CF₃ and B is a group represented by hydrogen, C(O)OR₁ or C(O)NR₁R₂ and D is represented by C(O)OR₁ or C(O)NR₁R₂, wherein R₁ and R₂ are each independently represented by hydrogen or C₁-C₆ alkyl by carrying out the reaction depicted in Reaction Scheme A in which D" is represented by C(O)OR₁' or C(O)NR₁R₂ wherein R₁' is C₁-C₆ alkyl, D' is represented by C(O)OH and X, Z, R₁ and R₂ are as above:D" = C(O)OR₁' or C(O)NR₁R₂R₁' =C₁-C₆ alkylD' = C(O)OHb) for those compounds wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃ and B is a group represented NHO(O)OR₃ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl or C(O)N₁R₂ wherein R₁ and R₂ are as previously defined, the compounds wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented NHC(O)R₃, NBC(O)NHR₃, NHSO₂CF₃, or NHSO₂C₆H₅ and D is represented by C(O)OR₁, wherein R₁ is hydrogen and the compounds wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF3, B is a group represented NH₂ and D is represented by C(O)OR₁, wherein R₁ is hydrogen by carrying out the reaction depicted in Reaction Scheme B in which B' is NHC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃ or NHSO₂C₆H₅, D' is C(O)R₁' or C(O)NR₁R₂ and R₁' is C₁-C₆ alkyl and A, Z, R₁, R₂ and R₃ are as above:B' = NHC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃ or NHSO₂C₆H₅D' = C(O)OR₁' or C(O)NR₁R₂R₁' = C₁-C₆ alkylc) for those compounds wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented NHC(O)OR₃ and D is represented by C(O)OR₁, wherein R₁ is hydrogen by carrying out the reaction depicted in Reaction Scheme C in which Z, A and R₃ are as above:d) for those compounds wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented NH₂, NHC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃, or NHSO₂C₆H₅ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl or C(O)NR₁R₂ by carrying out the reaction depicted in Reaction Scheme D in which B' is NHC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃ or NHSO₂C₆H₅, R₁' = C₁-C₆ alkyl and Z, A, R₁, R₂ and R₃ are as above:B' = NHC(O)R₃, NHC(O)NHR₃, NHSO₂CF₃ or NHSO₂C₆H₅R₁' = C₁-C₆ alkyle) for those compounds wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented by NR₁R₂ and D is represented by C(O)OR₁ wherein R₁ is hydrogen by carrying out the reaction depicted in Reaction Scheme E in which Z, A, R₁ and R₂ are as above:f) for those compounds wherein X is represented by a phenyl derivative, A is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, OCF₃, CF₃, B is a group represented by NR₁R₂ and D is represented by C(O)OR₁, wherein R₁ is C₁-C₆ alkyl, or C(O)NR₁R₂ by carrying out the reaction depicted in Reaction Scheme F in which R₁' is represented by C₁-C₆ alkyl and Z, A, R₁ and R₂ are as above:R₁' = C₁-C₆ alkyl ,
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US66178091A | 1991-02-27 | 1991-02-27 | |
US661780 | 1991-02-27 | ||
US70000491A | 1991-05-14 | 1991-05-14 | |
PCT/US1992/001093 WO1992015565A1 (en) | 1991-02-27 | 1992-02-11 | Nmda antagonists |
US700004 | 1996-08-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0573562A1 EP0573562A1 (en) | 1993-12-15 |
EP0573562B1 true EP0573562B1 (en) | 1996-04-24 |
Family
ID=27098383
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP92907466A Expired - Lifetime EP0573562B1 (en) | 1991-02-27 | 1992-02-11 | Dihydroquinoline NMDA antagonists |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0573562B1 (en) |
JP (1) | JP3465794B2 (en) |
KR (1) | KR100224045B1 (en) |
AT (1) | ATE137225T1 (en) |
AU (1) | AU660969B2 (en) |
CA (1) | CA2104297C (en) |
DE (1) | DE69210229T2 (en) |
DK (1) | DK0573562T3 (en) |
ES (1) | ES2089511T3 (en) |
FI (1) | FI103202B (en) |
GR (1) | GR3019772T3 (en) |
HU (1) | HU217425B (en) |
NO (1) | NO180485C (en) |
WO (1) | WO1992015565A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5318985A (en) * | 1991-12-20 | 1994-06-07 | Merrell Dow Pharmaceuticals Inc. | Potentiation of NMDA antagonists |
ATE404201T1 (en) * | 1992-06-22 | 2008-08-15 | Univ California | GLYCINE RECEPTOR ANTAGONISTS AND THEIR USE |
US5475007A (en) * | 1993-05-28 | 1995-12-12 | The Regents Of The University Of California | 1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 or 4-oximes and the use thereof |
DE69416324T2 (en) * | 1993-11-29 | 1999-06-10 | Merrell Pharmaceuticals Inc., Cincinnati, Ohio | HETEROCYCLIC BENZOLSULFONYLIMINE DERIVATIVES AS INHIBITORS OF THE IL-1 EFFECT |
ES2131297T3 (en) * | 1993-11-29 | 1999-07-16 | Merrell Pharma Inc | NEW BENZENE-SULPHONYLAMINE DERIVATIVES AS IL-1 ACTION INHIBITORS. |
CA2788656A1 (en) | 2010-02-16 | 2011-08-25 | Pfizer Inc. | (r)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2h-pyran-4-ol, a partial agonist of 5-ht4 receptors |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8719102D0 (en) * | 1987-08-12 | 1987-09-16 | Merck Sharp & Dohme | Therapeutic agents |
IL93610A0 (en) * | 1989-03-08 | 1990-12-23 | Merck Sharp & Dohme | Tetrahydroquinoline derivatives,their preparation and pharmaceutical compositions containing them |
ZA903588B (en) * | 1989-05-16 | 1991-02-27 | Merrell Dow Pharma | Excitatory amino acid antagonists |
-
1992
- 1992-02-11 WO PCT/US1992/001093 patent/WO1992015565A1/en active IP Right Grant
- 1992-02-11 ES ES92907466T patent/ES2089511T3/en not_active Expired - Lifetime
- 1992-02-11 KR KR1019930702559A patent/KR100224045B1/en not_active IP Right Cessation
- 1992-02-11 HU HU9302433A patent/HU217425B/en not_active IP Right Cessation
- 1992-02-11 AT AT92907466T patent/ATE137225T1/en not_active IP Right Cessation
- 1992-02-11 AU AU15320/92A patent/AU660969B2/en not_active Ceased
- 1992-02-11 DK DK92907466.4T patent/DK0573562T3/en active
- 1992-02-11 JP JP50728592A patent/JP3465794B2/en not_active Expired - Lifetime
- 1992-02-11 CA CA002104297A patent/CA2104297C/en not_active Expired - Lifetime
- 1992-02-11 DE DE69210229T patent/DE69210229T2/en not_active Expired - Lifetime
- 1992-02-11 EP EP92907466A patent/EP0573562B1/en not_active Expired - Lifetime
-
1993
- 1993-08-26 NO NO933042A patent/NO180485C/en not_active IP Right Cessation
- 1993-08-26 FI FI933762A patent/FI103202B/en active
-
1996
- 1996-04-25 GR GR960401099T patent/GR3019772T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO1992015565A1 (en) | 1992-09-17 |
AU660969B2 (en) | 1995-07-13 |
DE69210229D1 (en) | 1996-05-30 |
JP3465794B2 (en) | 2003-11-10 |
DE69210229T2 (en) | 1996-11-14 |
ATE137225T1 (en) | 1996-05-15 |
HU9302433D0 (en) | 1993-11-29 |
NO933042D0 (en) | 1993-08-26 |
NO180485C (en) | 1997-04-30 |
CA2104297A1 (en) | 1992-08-28 |
FI103202B1 (en) | 1999-05-14 |
HUT67301A (en) | 1995-03-28 |
GR3019772T3 (en) | 1996-07-31 |
DK0573562T3 (en) | 1996-05-13 |
NO180485B (en) | 1997-01-20 |
FI933762A (en) | 1993-08-26 |
AU1532092A (en) | 1992-10-06 |
EP0573562A1 (en) | 1993-12-15 |
FI933762A0 (en) | 1993-08-26 |
JPH06505746A (en) | 1994-06-30 |
HU217425B (en) | 2000-01-28 |
KR100224045B1 (en) | 1999-10-15 |
FI103202B (en) | 1999-05-14 |
ES2089511T3 (en) | 1996-10-01 |
CA2104297C (en) | 2003-05-27 |
KR930703257A (en) | 1993-11-29 |
NO933042L (en) | 1993-08-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU641052B2 (en) | 3-amidoindolyl derivatives | |
JP3664492B2 (en) | Tachikinin NK ▲ Lower 3 ▼ Quinoline derivatives as receptor antagonists | |
EP0922034B1 (en) | Tetrahydroquinoline derivatives as eaa antagonists | |
JP2000501104A (en) | Quinoline derivatives | |
CA2643070A1 (en) | Novel 1,2,3,4-tetrahydroquinoxaline derivative having glucocorticoid receptor binding activity | |
WO2008059866A1 (en) | Novel 1,2-dihydroquinoline derivative having substituted phenylamino lower alkyl group and ester-introduced phenyl group as substituents | |
WO2004004726A1 (en) | Mchir antagonists | |
EP0585500A1 (en) | Diaryl piperazineacetamides as antimuscarinic agents | |
EP0501378B1 (en) | NMDA Antagonists | |
EP0573562B1 (en) | Dihydroquinoline NMDA antagonists | |
KR0178281B1 (en) | 3-indolyl thioacetate derivatives | |
US5606063A (en) | NMDA antagonists | |
US5547991A (en) | NMDA antagonism method | |
US5360814A (en) | NMDA antagonists | |
CA2126076A1 (en) | Nitroquinolone derivatives as nmda antagonists | |
JP2022520631A (en) | 3,6-Disubstituted-2-pyridinealdoxime skeleton | |
HU215914B (en) | Process for preparing kynurenine derivatives with nmda antagonist activity and pharmaceutical compositions containing them | |
JP2003246732A (en) | Neurotmesis remedy comprising 1,2-ethanediol derivative or salt thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19930923 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL SE |
|
17Q | First examination report despatched |
Effective date: 19940121 |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: MERRELL PHARMACEUTICALS INC. |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL SE |
|
REF | Corresponds to: |
Ref document number: 137225 Country of ref document: AT Date of ref document: 19960515 Kind code of ref document: T |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: E. BLUM & CO. PATENTANWAELTE |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
ITF | It: translation for a ep patent filed | ||
REF | Corresponds to: |
Ref document number: 69210229 Country of ref document: DE Date of ref document: 19960530 |
|
ET | Fr: translation filed | ||
REG | Reference to a national code |
Ref country code: GR Ref legal event code: FG4A Free format text: 3019772 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2089511 Country of ref document: ES Kind code of ref document: T3 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2089511 Country of ref document: ES Kind code of ref document: T3 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed | ||
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DK Payment date: 20030120 Year of fee payment: 12 Ref country code: CH Payment date: 20030120 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20030121 Year of fee payment: 12 Ref country code: NL Payment date: 20030121 Year of fee payment: 12 Ref country code: AT Payment date: 20030121 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: MC Payment date: 20030128 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20030130 Year of fee payment: 12 Ref country code: GR Payment date: 20030130 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20030221 Year of fee payment: 12 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040211 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040211 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040212 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040228 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040228 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040229 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040229 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040301 |
|
BERE | Be: lapsed |
Owner name: *MERRELL PHARMACEUTICALS INC. Effective date: 20040228 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040901 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040903 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP |
|
EUG | Se: european patent has lapsed | ||
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 20040901 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20100325 AND 20100331 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20100401 AND 20100407 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20100408 AND 20100414 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20110218 Year of fee payment: 20 Ref country code: IT Payment date: 20110221 Year of fee payment: 20 Ref country code: DE Payment date: 20110208 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20110315 Year of fee payment: 20 Ref country code: GB Payment date: 20110209 Year of fee payment: 20 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R071 Ref document number: 69210229 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R071 Ref document number: 69210229 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: PE20 Expiry date: 20120210 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A Owner name: AVENTISUB II INC. Effective date: 20120302 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20120212 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20120210 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20140827 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20120212 |